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Sample records for er-positive breast tumors

  1. Discovery and verification of protein differences between Er positive/Her2/neu negative breast tumor tissue and matched adjacent normal breast tissue.

    PubMed

    Weitzel, Lindsay-Rae B; Byers, Tim; Allen, Jenna; Finlayson, Christina; Helmke, Steve M; Hokanson, John E; Hunsucker, Stephen W; Murphy, James R; Newell, Keri; Queensland, Kelly M; Singh, Meenakshi; Wischmeyer, Paul E; Duncan, Mark W; Elias, Anthony

    2010-11-01

    This study was designed to quantify and identify differences in protein levels between tumor and adjacent normal breast tissue from the same breast in 18 women with stage I/II ER positive/Her2/neu negative invasive breast cancer. Eighteen separate difference gel electrophoresis (DIGE) gels were run (1 gel per patient). Relative quantification was based on DIGE analysis. After excision and tryptic digestion, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and peptide mass mapping were used to identify protein spots. Two hundred and forty-three spots were differentially abundant between normal and cancer tissues. Fifty spots were identified: 41 were over abundant and nine were less abundant in cancers than in normal breast tissue. Western blotting provided independent confirmation for three of the most biologically and statistically interesting proteins. All 18 gels were replicated by another technician and 32% of the differentially abundant proteins were verified by the duplicate analysis. Follow-up studies are now examining these proteins as biomarkers in blood. PMID:20087651

  2. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

    PubMed

    Weir, Hazel M; Bradbury, Robert H; Lawson, Mandy; Rabow, Alfred A; Buttar, David; Callis, Rowena J; Curwen, Jon O; de Almeida, Camila; Ballard, Peter; Hulse, Michael; Donald, Craig S; Feron, Lyman J L; Karoutchi, Galith; MacFaul, Philip; Moss, Thomas; Norman, Richard A; Pearson, Stuart E; Tonge, Michael; Davies, Gareth; Walker, Graeme E; Wilson, Zena; Rowlinson, Rachel; Powell, Steve; Sadler, Claire; Richmond, Graham; Ladd, Brendon; Pazolli, Ermira; Mazzola, Anne Marie; D'Cruz, Celina; De Savi, Chris

    2016-06-01

    Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR. PMID:27020862

  3. A consensus prognostic gene expression classifier for ER positive breast cancer

    PubMed Central

    Teschendorff, Andrew E; Naderi, Ali; Barbosa-Morais, Nuno L; Pinder, Sarah E; Ellis, Ian O; Aparicio, Sam; Brenton, James D; Caldas, Carlos

    2006-01-01

    Background A consensus prognostic gene expression classifier is still elusive in heterogeneous diseases such as breast cancer. Results Here we perform a combined analysis of three major breast cancer microarray data sets to hone in on a universally valid prognostic molecular classifier in estrogen receptor (ER) positive tumors. Using a recently developed robust measure of prognostic separation, we further validate the prognostic classifier in three external independent cohorts, confirming the validity of our molecular classifier in a total of 877 ER positive samples. Furthermore, we find that molecular classifiers may not outperform classical prognostic indices but that they can be used in hybrid molecular-pathological classification schemes to improve prognostic separation. Conclusion The prognostic molecular classifier presented here is the first to be valid in over 877 ER positive breast cancer samples and across three different microarray platforms. Larger multi-institutional studies will be needed to fully determine the added prognostic value of molecular classifiers when combined with standard prognostic factors. PMID:17076897

  4. Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer.

    PubMed

    De Marchi, Tommaso; Foekens, John A; Umar, Arzu; Martens, John W M

    2016-07-01

    Estrogen receptor (ER)-positive breast cancer represents the majority (∼70%) of all breast malignancies. In this subgroup of breast cancers, endocrine therapies are effective both in the adjuvant and recurrent settings, although resistance remains a major issue. Several high-throughput approaches have been used to elucidate mechanisms of resistance and to derive potential predictive markers or alternative therapies. In this review, we cover the state-of-the-art of endocrine-resistance biomarker discovery with regard to the latest technological developments, and discuss current opportunities and restrictions for their implementation into a clinical setting. PMID:27233379

  5. Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers.

    PubMed

    Tsang, Julia Y S; Hui, Suen-Wah; Ni, Yun-Bi; Chan, Siu-Ki; Yamaguchi, Rin; Kwong, Ava; Law, Bonita K B; Tse, Gary M

    2014-01-01

    The value for lymphocytic infiltration (LI) has been increasingly recognized for tumor assessment. In breast cancer, however, the overall significance of LI remains poorly defined, probably due to its heterogeneity. A large cohort of breast cancer was evaluated for the degree of LI and its association with traditional pathologic factors, biomarker expression, and cancer subtypes. The number of CD8 cytotoxic effector and FoxP3 regulatory T cell (Treg) was evaluated in those cases with high LI. High LI was associated with negative ER and PR but positive HER2 and EGFR expression (p < 0.001 for all). In ER-positive cancers, high LI was associated with poor prognostic features including higher grade, the presence of necrosis, and lymphovascular invasion (LVI) (p = 0.007 for LVI and <0.001 for the others). Conversely, LI correlated with smaller tumor size, a good prognostic feature (p = 0.046) in HER2+ ER-cancers. These observations suggested LI may show opposite prognostic values in different breast cancer subgroups. Interestingly, when the phenotype of LI in these subgroups was evaluated, a strong positive association with intratumoral accumulation of Treg was found in ER-positive cancers (p = 0.003, Rs = 0.319), while the opposite was observed in HER2+ ER-cancers (p < 0.001, Rs = -0.427). Also, in ER-positive cancers, positive associations between peri- and intra-tumoral distribution were found with both CD8 and Tregs (CD8: p < 0.001, Rs = 0.547; Treg: p = 0.001, Rs = 0.460). Nonetheless, in HER2+ ER-cancers, such strong association was found with CD8 (p < 0.001, Rs = 0.766) but not Tregs. The results may implicate a differential intratumoral migration of LI in different subtypes of breast cancer. In summary, the clinical value of LI in breast cancers could be subtype-dependent. In ER-positive cancers, high LI correlated with biologic parameters associated with poor prognosis, whereas in HER2 positive cancers, LI correlated with biologic

  6. Benefit of low-dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS.

    PubMed

    Guerrieri-Gonzaga, Aliana; Sestak, Ivana; Lazzeroni, Matteo; Serrano, Davide; Rotmensz, Nicole; Cazzaniga, Massimiliano; Varricchio, Clara; Pruneri, Giancarlo; Leonardi, Maria Cristina; Orecchia, Roberto; Galimberti, Viviana; Bonanni, Bernardo; DeCensi, Andrea

    2016-11-01

    Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings. PMID:27381855

  7. Role of ERRF, a Novel ER-Related Nuclear Factor, in the Growth Control of ER-Positive Human Breast Cancer Cells

    PubMed Central

    Su, Dan; Fu, Xiaoying; Fan, Songqing; Wu, Xiao; Wang, Xin-Xin; Fu, Liya; Dong, Xue-Yuan; Ni, Jianping Jenny; Fu, Li; Zhu, Zhengmao; Dong, Jin-Tang

    2012-01-01

    Whereas estrogen–estrogen receptor α (ER) signaling plays an important role in breast cancer growth, it is also necessary for the differentiation of normal breast epithelial cells. How this functional conversion occurs, however, remains unknown. Based on a genome-wide sequencing study that identified mutations in several breast cancer genes, we examined some of the genes for mutations, expression levels, and functional effects on cell proliferation and tumorigenesis. We present the data for C1orf64 or ER-related factor (ERRF) from 31 cell lines and 367 primary breast cancer tumors. Whereas mutation of ERRF was infrequent (1 of 79 or 1.3%), its expression was up-regulated in breast cancer, and the up-regulation was more common in lower-stage tumors. In addition, increased ERRF expression was significantly associated with ER and/or progesterone receptor (PR) positivity, which was still valid in human epidermal growth factor receptor 2 (HER2)–negative tumors. In ER-positive tumors, ERRF expression was inversely correlated with HER2 status. Furthermore, higher ERRF protein expression was significantly associated with better disease-free survival and overall survival, particularly in ER- and/or PR-positive and HER2-negative tumors (luminal A subtype). Functionally, knockdown of ERRF in two ER-positive breast cancer cell lines, T-47D and MDA-MB-361, suppressed cell growth in vitro and tumorigenesis in xenograft models. These results suggest that ERRF plays a role in estrogen-ER–mediated growth of breast cancer cells and could, thus, be a potential therapeutic target. PMID:22341523

  8. ERRF is essential for Estrogen-Estrogen Receptor alpha signaling pathway in ER positive breast cancer cells.

    PubMed

    Luo, Ang; Zhang, Xuan

    2016-05-27

    Estrogen-Estrogen Receptor alpha (ERα) belongs to one of the most important signaling pathways controlling breast tissue development and progression of breast cancer. ERRF was recently identified as a candidate breast cancer associated protein and showed positive association with ERα status in clinical samples and cell lines. To further explore the relationship between ERRF and ERα, we studied whether ERRF plays any roles in estrogen-ERα pathway. Knockdown of ERRF in ER positive breast cancer cells T-47D and BT-474 reduced the level of p-AKT, p-MAPK, and phosphorylation of ERα at Ser 118 and Ser 167, and the transcriptional activity of ERα was inhibited as well. Further mechanism study proved ERRF to be an interacting partner of ERα. In total, these data revealed that ERRF is essential for the activity of E2-ERα pathway. PMID:27125460

  9. Navigating the Challenges of Endocrine Treatments in Premenopausal Women with ER-Positive Early Breast Cancer.

    PubMed

    Colleoni, Marco; Munzone, Elisabetta

    2015-08-01

    Endocrine therapy is a key component of adjuvant treatment for premenopausal patients with endocrine-responsive tumors. It is commonly well tolerated, although side effects are a main concern in the selection of treatment options. Tamoxifen is still considered an adequate endocrine therapy in a large group of premenopausal patients (e.g. lower-risk patient, presence of co-morbidities, patient preference). Results of the SOFT and TEXT trials addressing new adjuvant endocrine treatment options in premenopausal patients were recently presented. Overall, in the SOFT study the premenopausal population did not benefit from the addition of ovarian function suppression (OFS). Nevertheless, for women at sufficient risk of recurrence to receive adjuvant chemotherapy and who maintained premenopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. The magnitude of the effect was larger in younger patients. Moreover, in the SOFT and TEXT trials, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival. However, premenopausal patients include heterogeneous subsets of women and tumors where costs and benefits of adjuvant endocrine therapy should be properly weighted. Issues specific for premenopausal patients, related to desire for pregnancy, family planning, safety, quality of life and subjective side effects, should be a priority in the therapeutic algorithm. Therefore, selecting the best-tolerated agent can enhance adherence to therapies and reduce the impact on quality of life and health status for these younger patients. PMID:26177891

  10. Low Concordance between Gene Expression Signatures in ER Positive HER2 Negative Breast Carcinoma Could Impair Their Clinical Application

    PubMed Central

    Laas, Enora; Mallon, Peter; Duhoux, Francois P.; Hamidouche, Amina; Rouzier, Roman; Reyal, Fabien

    2016-01-01

    Background Numerous prognostic gene expression signatures have been recently described. Among the signatures there is variation in the constituent genes that are utilized. We aim to evaluate prognostic concordance among eight gene expression signatures, on a large dataset of ER positive HER2 negative breast cancers. Methods We analysed the performance of eight gene expression signatures on six different datasets of ER+ HER2- breast cancers. Survival analyses were performed using the Kaplan–Meier estimate of survival function. We assessed discrimination and concordance between the 8 signatures on survival and recurrence rates The Nottingham Prognostic Index (NPI) was used to to stratify the risk of recurrence/death. Results The discrimination ability of the whole signatures, showed fair discrimination performances, with AUC ranging from 0.64 (95%CI 0.55–0.73 for the 76-genes signatures, to 0.72 (95%CI 0.64–0.8) for the Molecular Prognosis Index T17. Low concordance was found in predicting events in the intermediate and high-risk group, as defined by the NPI. Low risk group was the only subgroup with a good signatures concordance. Conclusion Genomic signatures may be a good option to predict prognosis as most of them perform well at the population level. They exhibit, however, a high degree of discordance in the intermediate and high-risk groups. The major benefit that we could expect from gene expression signatures is the standardization of proliferation assessment. PMID:26895349

  11. DIFFERENCES IN THE TRANSCRIPTIONAL RESPONSE TO FULVESTRANT AND OESTROGEN DEPRIVATION IN ER-POSITIVE BREAST CANCER

    PubMed Central

    Patani, Neill; Dunbier, Anita; Anderson, Helen; Ghazoui, Zara; Ribas, Ricardo; Anderson, Elizabeth; Gao, Qiong; A’hern, Roger; Mackay, Alan; Lindemann, Justin; Wellings, Robert; Walker, Jill; Kuter, Irene; Martin, Lesley-Ann; Dowsett, Mitch

    2014-01-01

    Purpose Endocrine therapies include aromatase inhibitors and the selective oestrogen receptor (ER) down-regulator fulvestrant. This study aimed to determine if the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses. Experimental design Global gene expression profiles from ERα-positive breast carcinomas before and during pre-surgical treatment with fulvestrant (n=22) or anastrozole (n=81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and oestrogen (E) deprivation were identified and integrated using gene ontology (GO), pathway and network analyses to evaluate their potential significance. Results The overall transcriptional response to fulvestrant and E-deprivation was correlated (r=0.61 in pre-surgical studies, r=0.87 in vitro), involving down-regulation of E-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than E-deprivation (slope=0.62 in pre-surgical studies, slope=0.63 in vitro). Comparative analyses identified 28 genes and 40 GO categories affected specifically by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2 and NRP1, associated with ERα, androgen receptor (AR) and TP53, in a network regulating cell cycle, death, survival, and tumour morphology. Eighteen genes responding differently to fulvestrant specifically predicted anti-proliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio=0.29). Conclusions The transcriptional response to fulvestrant has much in common with E-deprivation, but is stronger with distinctions potentially attributable to arrest of E-independent ERα activity and involvement of AR signalling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent

  12. Kinome wide functional screen identifies role of Polo-like kinase 1 (PLK1) in hormone-independent, ER-positive breast cancer

    PubMed Central

    Bhola, Neil; Jansen, Valerie M.; Bafna, Sangeeta; Giltnane, Jennifer M.; Balko, Justin M.; Estrada, Mónica V.; Meszoely, Ingrid; Mayer, Ingrid; Abramson, Vandana; Ye, Fei; Sanders, Melinda; Dugger, Teresa C.; Van Allen, Eliezer; Arteaga, Carlos L.

    2014-01-01

    Estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens but eventually become estrogen-independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki67 score in primary ER+ breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacological inhibition of PLK1 with volasertib, a small molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared to parental MCF7 cells. Further, JUNB and BCL2L1 (which encodes anti-apoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER+ human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy. PMID:25480943

  13. A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer

    PubMed Central

    Bastos, E. P.; Brentani, H.; Pereira, C. A. B.; Polpo, A.; Lima, L.; Puga, R. D.; Pasini, F. S.; Osorio, C. A. B. T.; Roela, R. A.; Achatz, M. I.; Trapé, A. P.; Gonzalez-Angulo, A. M.; Brentani, M. M.

    2016-01-01

    genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC. PMID:27152840

  14. Integrated analysis of DNA methylation, immunohistochemistry and mRNA expression, data identifies a Methylation Expression Index (MEI) robustly associated with survival of ER-positive breast cancer patients

    PubMed Central

    Garcia-Closas, Montserrat; Davis, Sean; Meltzer, Paul; Lissowska, Jolanta; Horne, Hisani N.; Sherman, Mark E.; Lee, Maxwell

    2015-01-01

    Identification of prognostic gene expression signatures may enable improved decisions about management of breast cancer. To identify a prognostic signature for breast cancer, we performed DNA methylation profiling and identified methylation markers that were associated with expression of ER, PR, HER2, CK5/6 and EGFR proteins. Methylation markers that were correlated with corresponding mRNA expression levels were identified using 208 invasive tumors from a population-based case-control study conducted in Poland. Using this approach, we defined the Methylation Expression Index (MEI) signature that was based on a weighted sum of mRNA levels of 57 genes. Classification of cases as low or high MEI scores were related to survival using Cox regression models. In the Polish study, women with ER-positive low MEI cancers had reduced survival at a median of 5.20 years of follow-up, HR=2.85 95%CI=1.25-6.47. Low MEI was also related to decreased survival in four independent datasets totaling over 2500 ER-positive breast cancers. These results suggest that integrated analysis of tumor expression markers, DNA methylation, and mRNA data can be an important approach for identifying breast cancer prognostic signatures. Prospective assessment of MEI along with other prognostic signatures should be evaluated in future studies. PMID:25773928

  15. Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.

    PubMed

    Sanft, Tara; Aktas, Bilge; Schroeder, Brock; Bossuyt, Veerle; DiGiovanna, Michael; Abu-Khalaf, Maysa; Chung, Gina; Silber, Andrea; Hofstatter, Erin; Mougalian, Sarah; Epstein, Lianne; Hatzis, Christos; Schnabel, Cathy; Pusztai, Lajos

    2015-12-01

    Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I-III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45-87), 79% postmenopausal, 60% stage I). BCI predicted a low risk of late recurrence in 59% of patients versus intermediate/high in 24 and 17%, respectively. Physician recommendations for extended endocrine therapy changed for 26% of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54%. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction. PMID:26578401

  16. GATA3 mRNA expression, but not mutation, associates with longer progression-free survival in ER-positive breast cancer patients treated with first-line tamoxifen for recurrent disease.

    PubMed

    Liu, Jingjing; Prager-van der Smissen, Wendy J C; Look, Maxime P; Sieuwerts, Anieta M; Smid, Marcel; Meijer-van Gelder, Marion E; Foekens, John A; Hollestelle, Antoinette; Martens, John W M

    2016-06-28

    In breast cancer, GATA3 mutations have been associated with a favorable prognosis and the response to neoadjuvant aromatase inhibitor treatment. Therefore, we investigated whether GATA3 mutations predict the outcome of tamoxifen treatment in the advanced setting. In a retrospective study consisting of 235 hormone-naive patients with ER-positive breast cancer who received tamoxifen as first-line treatment for recurrent disease, GATA3 mutations (in 14.0% of patients) did not significantly associate with either the overall response rate (ORR) or with the length of progression-free survival (PFS) after the start of tamoxifen therapy. Interestingly, among 148 patients for whom both mutation and mRNA expression data were available, GATA3 mutations associated with an increased expression of GATA3. However, only 23.7% of GATA3 high tumors had a mutation. Evaluation of the clinical significance of GATA3 mRNA revealed that it was associated with prolonged PFS, but not with the ORR, also in multivariate analysis. Thus, GATA3 mRNA expression, but not GATA3 mutation, is an independent predictor of prolonged PFS in ER-positive breast cancer patients who received first-line tamoxifen for recurrent disease. Besides GATA3 mutation, other mechanisms must exist that underlie increased GATA3 levels. PMID:27018307

  17. Endocrine Therapy for Leptomeningeal Metastases from ER-Positive Breast Cancer: Case Report and a Review of the Literature.

    PubMed

    Zoghi, Behyar; Elledge, Richard

    2016-03-01

    Leptomeningeal disease is an uncommon complication of estrogen receptor positive breast cancer. While there is little consensus on the standard of care, recommendations from current clinical practice guidelines are to treat with intrathecal chemotherapy, necessitating invasive procedures and potentially resulting in a substantial incidence of serious complications and side effects. Here, we review all published evidence of the effectiveness of systemic hormonal therapy alone in treating this condition, with the advantage of requiring no invasive procedures and having virtually no serious complications or side effects. Evidence indicates that most hormonal therapies can penetrate the central nervous system and can be an effective treatment of endocrine sensitive breast cancer that is widely metastatic to the leptomeninges. PMID:26748605

  18. Comparison of 18F-FES, 18F-FDG, and 18F-FMISO PET Imaging Probes for Early Prediction and Monitoring of Response to Endocrine Therapy in a Mouse Xenograft Model of ER-Positive Breast Cancer

    PubMed Central

    Yang, ZhongYi; Zhang, JianPing; Zhang, YongPing; Luo, JianMin; Zhang, YingJian

    2016-01-01

    Background There is an increasing need to characterize biological processes for early prediction and monitoring of response to endocrine therapy in breast cancer using multiple positron emission tomography (PET) imaging probes. However, use of more than two PET tracers in a single clinical trial is quite challenging. In this study we carried out a longitudinal investigation of 18F-FES, 18F-FDG, and 18F-FMISO PET imaging probes for early prediction and monitoring of response to endocrine therapy in a mouse xenograft model of estrogen receptor (ER)-positive breast cancer. Method ER+ human breast cancer ZR-75-1 models were established in female mice that were then randomly assigned to a treatment (fulvestrant, 5.0 mg/week for 21 days) or vehicle group. Micro-PET/CT imaging with 18F-FES, 18F-FDG, and 18F-FMISO was performed on days 0, 3, 14, and 21 after treatment. The uptake value (percentage injected dose per gram, %ID/g) for each probe in tumor (T) tissue and contralateral muscle (M) was measured for quantitative analysis and T/M calculation. Tumor volume was measured to record tumor growth at each time point. Tumor tissues were sampled for immunohistochemical staining of ER expression. Correlations for tumor volume and ERα levels with uptake data for the probe were tested. Results Uptake data for 18F-FES in ZR-75-1 tumor tissues corresponded well with tumor response to endocrine therapy, but not for 18F-FDG and 18F-FMISO, according to longitudinal micro-PET/CT imaging and quantitative correlation analysis. There was a significant positive correlation between 18F-FES uptake and ER levels (%ID/gmax r2 = 0.76, P< 0.05; T/M r2 = 0.82, P<0.05). Notably, 18F-FES uptake on day 3 was significantly correlated with the day 21/baseline tumor volume ratio (%ID/gmax r2 = 0.74, P < 0.05; T/M r2 = 0.78, P < 0.05). Conclusions Comparison of 18F-FES, 18F-FDG, and 18F-FMISO probes revealed that 18F-FES PET/CT molecular imaging can provide a precise early prediction of tumor

  19. RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer.

    PubMed

    Chimge, Nyam-Osor; Little, Gillian H; Baniwal, Sanjeev K; Adisetiyo, Helty; Xie, Ying; Zhang, Tian; O'Laughlin, Andie; Liu, Zhi Y; Ulrich, Peaches; Martin, Anthony; Mhawech-Fauceglia, Paulette; Ellis, Matthew J; Tripathy, Debu; Groshen, Susan; Liang, Chengyu; Li, Zhe; Schones, Dustin E; Frenkel, Baruch

    2016-01-01

    Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER(+)) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1's second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER(+) mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER(+) breast cancer. PMID:26916619

  20. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

    PubMed Central

    Spoerke, Jill M.; Gendreau, Steven; Walter, Kimberly; Qiu, Jiaheng; Wilson, Timothy R.; Savage, Heidi; Aimi, Junko; Derynck, Mika K.; Chen, Meng; Chan, Iris T.; Amler, Lukas C.; Hampton, Garret M.; Johnston, Stephen; Krop, Ian; Schmid, Peter; Lackner, Mark R.

    2016-01-01

    Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study. PMID:27174596

  1. RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer

    PubMed Central

    Chimge, Nyam-Osor; Little, Gillian H.; Baniwal, Sanjeev K.; Adisetiyo, Helty; Xie, Ying; Zhang, Tian; O'Laughlin, Andie; Liu, Zhi Y.; Ulrich, Peaches; Martin, Anthony; Mhawech-Fauceglia, Paulette; Ellis, Matthew J.; Tripathy, Debu; Groshen, Susan; Liang, Chengyu; Li, Zhe; Schones, Dustin E.; Frenkel, Baruch

    2016-01-01

    Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER+) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1's second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER+ mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER+ breast cancer. PMID:26916619

  2. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

    PubMed Central

    Sarfstein, Rive; Belfiore, Antonino; Werner, Haim

    2010-01-01

    The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells. PMID:24281069

  3. Stage-Specific MicroRNAs and Their Role in the Anticancer Effects of Calorie Restriction in a Rat Model of ER-Positive Luminal Breast Cancer.

    PubMed

    Devlin, Kaylyn L; Sanford, Tiffany; Harrison, Lauren M; LeBourgeois, Paul; Lashinger, Laura M; Mambo, Elizabeth; Hursting, Stephen D

    2016-01-01

    MicroRNAs have emerged as ubiquitous post-transcriptional regulators that coordinate many fundamental processes within cells, including those commonly linked to cancer when dysregulated. Profiling microRNAs across stages of cancer progression provides focus as to which microRNAs are key players in cancer development and are therefore important to manipulate with interventions to delay cancer onset and progression. Calorie restriction is one of the most effective preventive interventions across many types of cancer, although its effects on microRNAs have not been well characterized. We used the dimethylbenz[a]-anthracene-induced model of luminal mammary cancer in Sprague Dawley rats to elucidate which microRNAs are linked to progression in this type of cancer and, subsequently, to study how calorie restriction affects such microRNAs. We identified eight microRNAs (miR-10a, miR-10b, miR-21, miR-124, miR-125b, miR-126, miR-145 and miR-200a) to be associated with DMBA-induced mammary tumor progression. Calorie restriction, which greatly increased tumor-free survival and decreased the overall size of tumors that did develop, significantly decreased the expression of one microRNA, miR-200a, which was positively associated with tumor progression. We further showed that inhibition of miR-200a function, mimicking the effect of calorie restriction on this microRNA, inhibited proliferation in both rat (LA7) and human (MCF7) luminal mammary cancer cell lines. These findings present, for the first time, a stage-specific profile of microRNAs in a rodent model of luminal mammary cancer. Furthermore, we have identified the regulation of miR-200a, a microRNA that is positively associated with progression in this model, as a possible mechanism contributing to the anticancer effects of calorie restriction. PMID:27433802

  4. Stage-Specific MicroRNAs and Their Role in the Anticancer Effects of Calorie Restriction in a Rat Model of ER-Positive Luminal Breast Cancer

    PubMed Central

    Devlin, Kaylyn L.; Sanford, Tiffany; Harrison, Lauren M.; LeBourgeois, Paul; Lashinger, Laura M.; Mambo, Elizabeth; Hursting, Stephen D.

    2016-01-01

    MicroRNAs have emerged as ubiquitous post-transcriptional regulators that coordinate many fundamental processes within cells, including those commonly linked to cancer when dysregulated. Profiling microRNAs across stages of cancer progression provides focus as to which microRNAs are key players in cancer development and are therefore important to manipulate with interventions to delay cancer onset and progression. Calorie restriction is one of the most effective preventive interventions across many types of cancer, although its effects on microRNAs have not been well characterized. We used the dimethylbenz[a]-anthracene-induced model of luminal mammary cancer in Sprague Dawley rats to elucidate which microRNAs are linked to progression in this type of cancer and, subsequently, to study how calorie restriction affects such microRNAs. We identified eight microRNAs (miR-10a, miR-10b, miR-21, miR-124, miR-125b, miR-126, miR-145 and miR-200a) to be associated with DMBA-induced mammary tumor progression. Calorie restriction, which greatly increased tumor-free survival and decreased the overall size of tumors that did develop, significantly decreased the expression of one microRNA, miR-200a, which was positively associated with tumor progression. We further showed that inhibition of miR-200a function, mimicking the effect of calorie restriction on this microRNA, inhibited proliferation in both rat (LA7) and human (MCF7) luminal mammary cancer cell lines. These findings present, for the first time, a stage-specific profile of microRNAs in a rodent model of luminal mammary cancer. Furthermore, we have identified the regulation of miR-200a, a microRNA that is positively associated with progression in this model, as a possible mechanism contributing to the anticancer effects of calorie restriction. PMID:27433802

  5. Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies

    PubMed Central

    Kwon, Youngjoo

    2014-01-01

    Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors. PMID:25493176

  6. Alcohol Consumption and Risk of Breast Cancer by Tumor Receptor Expression.

    PubMed

    Wang, Jun; Zhang, Xuehong; Beck, Andrew H; Collins, Laura C; Chen, Wendy Y; Tamimi, Rulla M; Hazra, Aditi; Brown, Myles; Rosner, Bernard; Hankinson, Susan E

    2015-12-01

    In epidemiologic studies, alcohol consumption appears more strongly associated with risk of estrogen receptor (ER)-positive than ER-negative breast cancer. However, this association has not been assessed by other potentially relevant tumor markers, such as androgen receptor (AR) or insulin receptor (IR). In the prospective Nurses' Health Study cohort, we evaluated alcohol consumption and breast cancer risk by individual tumor marker expression (i.e., ER, progesterone receptor [PR], AR, and IR) while controlling for other markers and also assessed the joint effect of these receptors. During 26 years follow-up of 106,037 women, 2552 invasive breast cancers contributed to the analysis. When all four markers were considered simultaneously, no significant heterogeneity of the alcohol and breast cancer association was observed by any of the markers. However, each increment in one drink per day was associated with 10% (95% confidence interval [CI] = 4%, 15%) and 9% (95% CI = 4%, 15%) increased risk of AR-positive and ER-positive breast cancer, respectively, while no increased risk was observed among AR-negative or ER-negative tumors. The association was independent of PR and IR expression. Assessment of the joint expression of hormone receptors revealed a significantly increased risk among AR+/ER+/PR+ (hazard ratio [HR] per drink/day = 1.11, 95% CI = 1.06, 1.17) but not in other subgroups (e.g. , AR-/ER-/PR-: HR = 0.99; 95% CI = 0.88, 1.12). Our data suggest that the alcohol and breast cancer association may be more pronounced among ER-positive and/or AR-positive breast tumors. However, our data do not support an important role of IR in the association. PMID:26385458

  7. Tumor apparent diffusion coefficient as an imaging biomarker to predict tumor aggressiveness in patients with estrogen-receptor-positive breast cancer.

    PubMed

    Shin, Hee Jung; Kim, So Hee; Lee, Hee Jin; Gong, Gyungyub; Baek, Seunghee; Chae, Eun Young; Choi, Woo Jung; Cha, Joo Hee; Kim, Hak Hee

    2016-08-01

    The purpose of this retrospective study was to evaluate whether tumor apparent diffusion coefficient (ADC) was correlated with pathologic biomarkers such as tumor cellularity, Ki67, tumor-infiltrating lymphocytes (TILs), and peritumoral lymphocytic infiltrate (PLI) in patients with estrogen receptor (ER)-positive breast cancer. The study was approved by the institutional review board and informed consent was waived. From July 2014 to December 2014, we reviewed 140 ER-positive tumors in 138 consecutive patients (range, 28-77 years; mean, 52 years) who underwent preoperative breast MRI and definitive surgery. All patients underwent diffusion-weighted imaging with a 3T scanner. Two radiologists drew the region of interest of the entire tumor and obtained the mean and pixel-based histogram of ADC. On pathology, two pathologists reviewed tumor cellularity, Ki67, TILs, and PLI. Multiple linear regression analysis was used to determine pathologic variables independently associated with ADC. Tumors with high tumor cellularity and high Ki67 had significantly lower ADCs than those with low tumor cellularity and low Ki67 (P < 0.05 for all). Tumors without PLI had significantly higher standard deviation than those with PLI (0.23 ± 0.08 versus 0.18 ± 0.05; P < 0.001). Median ADC was negatively correlated with tumor cellularity (r = -0.441), and Ki67 (r = -0.382). The standard deviation of ADC was also negatively correlated with the degree of PLI (r = -0.319). On multivariate linear regression analysis, tumor cellularity and Ki67 were independently associated with tumor ADC. Tumor ADC would be an MRI biomarker for the prediction of tumor aggressiveness indicators such as Ki67, tumor cellularity, and PLI in ER-positive breast cancer. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27332719

  8. Body Mass Index is Associated with Gene Methylation in Estrogen Receptor-Positive Breast Tumors

    PubMed Central

    Hair, Brionna Y.; Troester, Melissa A.; Edmiston, Sharon N.; Parrish, Eloise A.; Robinson, Whitney R.; Wu, Michael C.; Olshan, Andrew F.; Swift-Scanlan, Theresa; Conway, Kathleen

    2015-01-01

    Background Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors. Methods Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from Phase I of the Carolina Breast Cancer Study, a population based case-control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor status was also conducted. Results In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with differential methylation (false discovery rate q-value < 0.05) in just 2 gene loci in breast tumor tissue overall and in 21 loci among estrogen receptor (ER)-positive tumors. Obesity was associated with methylation of genes that function in immune response, cell growth, and DNA repair. Conclusions Obesity is associated with altered methylation overall, and with hypermethylation among ER-positive tumors in particular, suggesting that obesity may influence the methylation of genes with known relevance to cancer. Some of these differences in methylation by obese status may influences levels of gene expression within breast cells. Impact If our results are validated, obesity-associated methylation sites could serve as targets for prevention and treatment research. PMID:25583948

  9. The 5p12 breast cancer susceptibility locus affects MRPS30 expression in estrogen-receptor positive tumors

    PubMed Central

    Quigley, David A.; Fiorito, Elisa; Nord, Silje; Van Loo, Peter; Alnæs, Grethe Grenaker; Fleischer, Thomas; Tost, Jorg; Vollan, Hans Kristian Moen; Tramm, Trine; Overgaard, Jens; Bukholm, Ida R; Hurtado, Antoni; Balmain, Allan; Børresen-Dale, Anne-Lise; Kristensen, Vessela

    2014-01-01

    Genome-wide association studies have identified numerous loci linked to breast cancer susceptibility, but the mechanism by which variations at these loci influence susceptibility is usually unknown. Some variants are only associated with particular clinical subtypes of breast cancer. Understanding how and why these variants influence subtype-specific cancer risk contributes to our understanding of cancer etiology. We conducted a genome-wide expression Quantitative Trait Locus (eQTL) study in a discovery set of 287 breast tumors and 97 normal mammary tissue samples and a replication set of 235 breast tumors. We found that the risk-associated allele of rs7716600 in the 5p12 estrogen receptor-positive (ER-positive) susceptibility locus was associated with elevated expression of the nearby gene MRPS30 exclusively in ER-positive tumors. We replicated this finding in 235 independent tumors. Further, we showed the rs7716600 risk genotype was associated with decreased MRPS30 promoter methylation exclusively in ER-positive breast tumors. In vitro studies in MCF-7 cells carrying the protective genotype showed that estrogen stimulation decreased MRPS30 promoter chromatin availability and mRNA levels. In contrast, in 600MPE cells carrying the risk genotype, estrogen increased MRPS30 expression and did not affect promoter availability. Our data suggest the 5p12 risk allele affects MRPS30 expression in estrogen-responsive tumor cells after tumor initiation by a mechanism affecting chromatin availability. These studies emphasize that the genetic architecture of breast cancer is context-specific, and integrated analysis of gene expression and chromatin remodeling in normal and tumor tissues will be required to explain the mechanisms of risk alleles. PMID:24388359

  10. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

    PubMed

    Figueroa, Jonine D; Garcia-Closas, Montserrat; Humphreys, Manjeet; Platte, Radka; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Hammet, Fleur; Schmidt, Marjanka K; Broeks, Annegien; Tollenaar, Rob A E M; Van't Veer, Laura J; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Strick, Reiner; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Burwinkel, Barbara; Marme, Federik; Schneeweiss, Andreas; Sohn, Christof; Bojesen, Stig; Flyger, Henrik; Nordestgaard, Børge G; Benítez, Javier; Milne, Roger L; Ignacio Arias, Jose; Zamora, M Pilar; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Rahman, Nazneen; Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Yuri I; Karstens, Johann Hinrich; Bermisheva, Marina; Prokofieva, Darya; Gantcev, Shamil Hanafievich; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Soini, Ylermi; Kataja, Vesa; Lambrechts, Diether; Yesilyurt, Betül T; Chrisiaens, Marie-Rose; Peeters, Stephanie; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Couch, Fergus; Lee, Adam M; Diasio, Robert; Wang, Xianshu; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Maclean, Catriona; Offit, Ken; Robson, Mark; Joseph, Vijai; Gaudet, Mia; John, Esther M; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene; Knight, Julia A; Mulligan, Anna Marie; O'Malley, Frances P; Brinton, Louise A; Sherman, Mark E; Lissowska, Jolanta; Chanock, Stephen J; Hooning, Maartje; Martens, John W M; van den Ouweland, Ans M W; Collée, J Margriet; Hall, Per; Czene, Kamila; Cox, Angela; Brock, Ian W; Reed, Malcolm W R; Cross, Simon S; Pharoah, Paul; Dunning, Alison M; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Shen, Chen-Yang; Ding, Shian-ling; Hsu, Huan-Ming; Yu, Jyh-Cherng; Anton-Culver, Hoda; Ziogas, Argyrios; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Orr, Nick; Trentham-Dietz, Amy; Egan, Kathleen; Newcomb, Polly; Titus-Ernstoff, Linda; Easton, Doug; Spurdle, Amanda B

    2011-12-01

    A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer. PMID:21852249

  11. Phyllodes tumor of the breast

    PubMed Central

    Herazo, Fernando; Gil, Monica; Echeverri, Carolina; Ángel, Gonzalo; Borrero, Mauricio; Madrid, Jorge; Jaramillo, Ricardo

    2015-01-01

    Introduction: Breast Phyllodes tumors are rare breast tumors present in less than 1% of new cases of breast cancer, usually occurring among middle-aged women (40-50 yrs). Objective: This study shows diagnostic experience, surgical management and follows up of patients with this disease during a period of ten years in a oncology referral center. Methods: Retrospectively, breast cancer registries at the institution were reviewed, identifying 77 patients with Phyllodes tumors between 2002 and 2012, who had been operated on at the Instituto de Cancerología - Clínica Las Américas, in Medellín (Colombia). Clinical and histopathological data belonging to these cases was captured and analyzed and descriptive statistics were used. Results: The follow up median was 22.5 months (IQR: 10.5-60.0), average age was 47.2 yrs (SD: 12.4), mean tumor size was 3.6 cm (SD: 4.6), 88.3% of the patients (68 cases) presented negative margins and none of them received adjuvant chemotherapy. Of the patients with Phyllodes tumors; 33.8% had benign, 31.2% had borderline and 35.0% had malignant tumor. Disease-free survival was 85.8% and overall survival was 94.5%. Discussion: Reported data in this article is in accordance with what has been reported in worldwide literature. In our cohort even the high mean size of the tumors, the risk of local relapse and metastatic disease is low than previously reported in literature. Trials with longer follow up and molecular trials in Phyllodes tumors are necessary to understand the behavior of these tumors in Hispanics population. PMID:26600624

  12. Estrogen Receptor and HER2 Status on Disseminated Tumor Cells and Primary Tumor in Patients with Early Breast Cancer

    PubMed Central

    Jäger, Bernadette A.S.; Finkenzeller, Charlotte; Bock, Carolin; Majunke, Leonie; Jueckstock, Julia K.; Andergassen, Ulrich; Neugebauer, Julia K.; Pestka, Aurelia; Friedl, Thomas W.P.; Jeschke, Udo; Janni, Wolfgang; Doisneau-Sixou, Sophie F.; Rack, Brigitte K.

    2015-01-01

    BACKGROUND: We evaluated both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disseminated tumor cells (DTCs) in the bone marrow of 54 patients with early breast cancer and compared these with the corresponding primary tumor (PT). MATERIALS AND METHODS: Bone marrow aspirates were obtained at the time of first surgery, and ER and HER2 status on DTCs was assessed simultaneously by immunocytochemistry using a triple fluorescence staining method. RESULTS: The median number of DTCs was 13 (range 1-95). The concordance rate between ER status on DTC and PT was 74%. Patients with an ER-positive PT were significantly more likely to have at least one ER-positive DTC (34 out of 42) than patients with an ER-negative PT (6 out of 12; P = .031). Thirty-nine (93%) of the 42 patients with ER-positive PT had at least one ER-negative DTC. The concordance rate between HER2 status on DTC and PT was 52%. The probability of having at least one HER2-positive DTC was not related to the HER2 status of the PT (P = 0.56). Twenty-two (46%) of the 48 patients with a HER2-negative PT had at least one HER2-positive DTC. All the six patients with a HER2-positive PT had at least one HER2-negative DTC. CONCLUSION: Taken together, our study confirms that ER and/or HER2 status may differ between DTC and PT. This discordance could be important for patients lacking ER or HER2 expression on the PT but showing ER-positive or HER2-positive DTC because they might benefit from an endocrine and/or HER2-targeted therapy. PMID:26692533

  13. An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway.

    PubMed

    Sulaiman, Nurfarhanah Bte Syed; Mohan, Chakrabhavi Dhananjaya; Basappa, Salundi; Pandey, Vijay; Rangappa, Shobith; Bharathkumar, Hanumantharayappa; Kumar, Alan Prem; Lobie, Peter E; Rangappa, Kanchugarakoppal S

    2016-09-01

    Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present the anticancer activity of 2-(1-(4-(2-cyanophenyl)1-benzyl‑1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) against breast cancer cells. We observed that CIMO suppresses the proliferation of both estrogen receptor-negative (ER-) (BT-549, MDA-MB‑231) and estrogen receptor-positive (ER+) (MCF-7, and BT-474) breast cancer (BC) cells with IC50 of 3.05, 3.41, 4.12 and 4.19 µM, respectively, and without significantly affecting the viability of normal cells. CIMO was observed to mediate its anti-proliferative effect in ER- BC cells by inhibiting the phosphorylation of JAK2 and STAT3 proteins. Quantitative PCR analysis demonstrated that CIMO decreases the relative mRNA expression of genes that are involved in cell cycle progression (CCND1) and cell survival (BCL2, BCL-xL, BAD, CASP 3/7/9, and TP53). In addition, CIMO was observed to arrest BC cells at G0/G1 phase and of the cell cycle. Furthermore, CIMO suppressed BC cell migration and invasion with concordant regulation of genes involved in epithelial to mesechymal transition (CDH1, CDH2, OCLN and VIM). Thus, we report the utility of a synthetic azaspirane which targets the JAK-STAT pathway in ER- BC. PMID:27500741

  14. Phyllodes Tumor of the Breast

    SciTech Connect

    Belkacemi, Yazid Bousquet, Guilhem; Marsiglia, Hugo; Ray-Coquard, Isabelle; Magne, Nicolas; Malard, Yann; Lacroix, Magalie; Gutierrez, Cristina; Senkus, Elzbieta; Christie, David; Drumea, Karen; Lagneau, Edouard; Kadish, Sidney P.; Scandolaro, Luciano; Azria, David; Ozsahin, Mahmut

    2008-02-01

    Purpose: To better identify prognostic factors for local control and survival, as well as the role of different therapeutic options, for phyllodes tumors, a rare fibroepithelial neoplasm of the breast. Methods and Materials: Data from 443 women treated between 1971 and 2003 were collected from the Rare Cancer Network. The median age was 40 years (range, 12-87 years). Tumors were benign in 284 cases (64%), borderline in 80 cases (18%), and malignant in 79 cases (18%). Surgery consisted of breast-conserving surgery (BCS) in 377 cases (85%) and total mastectomy (TM) in 66 cases (15%). Thirty-nine patients (9%) received adjuvant radiotherapy (RT). Results: After a median follow-up of 106 months, local recurrence (LR) and distant metastases rates were 19% and 3.4%, respectively. In the malignant and borderline group (n = 159), RT significantly decreased LR (p = 0.02), and TM had better results than BCS (p = 0.0019). Multivariate analysis revealed benign histology, negative margins, and no residual disease (no RD) after initial treatment and RT delivery as independent favorable prognostic factors for local control; benign histology and low number of mitosis for disease-free survival; and pathologic tumor size tumor necrosis for overall survival. In the malignant and borderline subgroup multivariate analysis TM was the only favorable independent prognostic factor for disease-free survival. Conclusions: This study showed that phyllodes tumor patients with no RD after treatment have better local control. Benign tumors have a good prognosis after surgery alone. In borderline and malignant tumors, TM had better results than BCS. Thus, in these forms adjuvant RT should be considered according to histologic criteria.

  15. Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status

    PubMed Central

    Lidfeldt, Jon; Bendahl, Pär-Ola; Forsare, Carina; Malmström, Per; Fernö, Mårten; Belting, Mattias

    2015-01-01

    Experimental models implicate protease activated receptors (PARs) as important sensors of the proteolytic tumor microenvironment during breast cancer development. However, the role of the major PARs, PAR-1 and PAR-2, in human breast tumors remains to be elucidated. Here, we have investigated how PAR-1 and PAR-2 protein expression correlate with established clinicopathological variables and patient outcome in a well-characterized cohort of 221 breast cancer patients. Univariable and multivariable hazard ratios (HR) were estimated by the Cox proportional hazards model, distant disease-free survival (DDFS) and overall survival by the Kaplan–Meier method, and survival in different strata was determined by the log-rank test. Associations between PARs and clinicopathological variables were analyzed using Pearson’s χ2-test. We find that PAR-2 associates with DDFS (HR = 3.1, P = 0.003), whereas no such association was found with PAR-1 (HR = 1.2, P = 0.6). Interestingly, the effect of PAR-2 was confined to the ER-positive sub-group (HR = 5.5, P = 0.003 vs. HR = 1.2 in ER-negative; P = 0.045 for differential effect), and PAR-2 was an independent prognostic factor specifically in ER-positive tumors (HR = 3.9, P = 0.045). On the contrary, PAR-1 correlated with worse prognosis specifically in the ER-negative group (HR = 2.6, P = 0.069 vs. HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect). This study provides novel insight into the respective roles of PAR-1 and PAR-2 in human breast cancer and suggests a hitherto unknown association between PARs and ER signaling that warrants further investigation. PMID:26244666

  16. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium†

    PubMed Central

    Figueroa, Jonine D.; Garcia-Closas, Montserrat; Humphreys, Manjeet; Platte, Radka; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Hammet, Fleur; Schmidt, Marjanka K.; Broeks, Annegien; Tollenaar, Rob A.E.M.; Van't Veer, Laura J.; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Strick, Reiner; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Burwinkel, Barbara; Marme, Federik; Schneeweiss, Andreas; Sohn, Christof; Bojesen, Stig; Flyger, Henrik; Nordestgaard, Børge G.; Benítez, Javier; Milne, Roger L.; Ignacio Arias, Jose; Zamora, M. Pilar; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Rahman, Nazneen; Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Yuri I.; Karstens, Johann Hinrich; Bermisheva, Marina; Prokofieva, Darya; Hanafievich Gantcev, Shamil; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Soini, Ylermi; Kataja, Vesa; Lambrechts, Diether; Yesilyurt, Betül T.; Chrisiaens, Marie-Rose; Peeters, Stephanie; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Couch, Fergus; Lee, Adam M.; Diasio, Robert; Wang, Xianshu; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Maclean, Catriona; Offit, Ken; Robson, Mark; Joseph, Vijai; Gaudet, Mia; John, Esther M.; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene; Knight, Julia A.; Marie Mulligan, Anna; O'Malley, Frances P.; Brinton, Louise A.; Sherman, Mark E.; Lissowska, Jolanta; Chanock, Stephen J.; Hooning, Maartje; Martens, John W.M.; van den Ouweland, Ans M.W.; Collée, J. Margriet; Hall, Per; Czene, Kamila; Cox, Angela; Brock, Ian W.; Reed, Malcolm W.R.; Cross, Simon S.; Pharoah, Paul; Dunning, Alison M.; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Shen, Chen-Yang; Ding, Shian-ling; Hsu, Huan-Ming; Yu, Jyh-Cherng; Anton-Culver, Hoda; Ziogas, Argyrios; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Orr, Nick; Trentham-Dietz, Amy; Egan, Kathleen; Newcomb, Polly; Titus-Ernstoff, Linda; Easton, Doug; Spurdle, Amanda B.

    2011-01-01

    A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r2= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10–1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98–1.07, case-only P-heterogeneity = 7.6 × 10−5]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10−3) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer. PMID:21852249

  17. HER4 Selectively Coregulates Estrogen Stimulated Genes Associated with Breast Tumor Cell Proliferation

    PubMed Central

    Han, Wen; Jones, Frank E.

    2014-01-01

    The EGFR-family member HER4 undergoes regulated intramembrane proteolysis (RIP) to generate an intracellular domain (4ICD) that functions as a transcriptional coactivator. Accordingly, 4ICD coactivates the estrogen receptor (ER) and associates with ER at target gene promoters in breast tumor cells. However, the extent of 4ICD coactivation of ER and the functional significance of the 4ICD/ER transcriptional complex is unclear. To identify 4ICD coactivated genes we performed a microarray gene expression analysis of β-estradiol treated cells comparing control MCF-7 breast cancer cells to MCF-7 cells where HER4 expression was stably suppressed using a shRNA. In the MCF-7 cell line, β-estradiol significantly stimulated or repressed by 2-fold or more 726 or 53 genes, respectively. Significantly, HER4/4ICD was an obligate coactivator for 277 or 38% of the β-estradiol stimulated genes. Ingenuity Pathway Analysis of β-estradiol regulated genes identified significant associations with multiple cellular functions regulating cellular growth and proliferation, cell cycle progression, cancer metastasis, decreased hypoplasia, tumor cell migration, apoptotic resistance of tumor cells, and increased transcription. Genes coactivated by 4ICD displayed functional specificity by only significantly contributing to cellular growth and proliferation, cell cycle progression, and decreased hypoplasia. In direct concordance with these in situ results we show that HER4 knockdown in MCF-7 cells results in a loss of estrogen stimulated tumor cell proliferation and cell cycle progression, whereas, estrogen stimulated tumor cell migration was unaffected by loss of HER4 expression. In summary, we demonstrate for the first time that a cell surface receptor functions as an obligate ER coactivator with functional specificity associated with breast tumor cell proliferation and cell cycle progression. Nearly 90% of ER positive tumors coexpress HER4, therefore we predict that the majority of breast

  18. Genomic tumor evolution of breast cancer.

    PubMed

    Sato, Fumiaki; Saji, Shigehira; Toi, Masakazu

    2016-01-01

    Owing to recent technical development of comprehensive genome-wide analysis such as next generation sequencing, deep biological insights of breast cancer have been revealed. Information of genomic mutations and rearrangements in patients' tumors is indispensable to understand the mechanism in carcinogenesis, progression, metastasis, and resistance to systemic treatment of breast cancer. To date, comprehensive genomic analyses illustrate not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course from non-invasive disease via invasive primary tumor to metastatic tumor, and during treatment exposure. The accumulation pattern of base substitution and genomic rearrangement looks gradual and punctuated, respectively, in analogy with contrasting theories for evolution manner of species, Darwin's phyletic gradualism, and Eldredge and Gould's "punctuated equilibrium". Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer. Genomic mutation patterns in circulating tumor cells and circulating cell-free tumor DNA represent those of tumors existing in patient body. Liquid biopsy methods are now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of 'tumor evolution', is summarized. PMID:25998191

  19. Prospective sonographic study of 3093 breast tumors.

    PubMed

    Chao, T C; Lo, Y F; Chen, S C; Chen, M F

    1999-05-01

    To evaluate the predictive ability of sonographic tumor characteristics to differentiate benign from malignant tumors, we examined 3093 breast tumors (2360 benign and 733 malignant tumors) with ultrasonography. The ratio of the longest dimension to the anteroposterior diameter of benign tumors was significantly larger than that of malignant tumors (1.88+/-0.1 versus 1.69+/-0.02, P < 0.0001). Shape, margins, echogenicity, internal echo pattern, retrotumor acoustic shadowing, compressibility, and microcalcification were significant factors in the logistic regression model. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of breast sonography for malignancy were 86.1, 66.1, 44.1, 93.9, and 70.8%, respectively. Biopsy of the tumor for pathologic diagnosis is recommended if sonographic features are suggestive of malignancy. PMID:10327015

  20. Genomic landscapes of breast fibroepithelial tumors.

    PubMed

    Tan, Jing; Ong, Choon Kiat; Lim, Weng Khong; Ng, Cedric Chuan Young; Thike, Aye Aye; Ng, Ley Moy; Rajasegaran, Vikneswari; Myint, Swe Swe; Nagarajan, Sanjanaa; Thangaraju, Saranya; Dey, Sucharita; Nasir, Nur Diyana Md; Wijaya, Giovani Claresta; Lim, Jing Quan; Huang, Dachuan; Li, Zhimei; Wong, Bernice Huimin; Chan, Jason Yong Sheng; McPherson, John R; Cutcutache, Ioana; Poore, Gregory; Tay, Su Ting; Tan, Wai Jin; Putti, Thomas Choudary; Ahmad, Buhari Shaik; Iau, Philip; Chan, Ching Wan; Tang, Anthony P H; Yong, Wei Sean; Madhukumar, Preetha; Ho, Gay Hui; Tan, Veronique Kiak Mien; Wong, Chow Yin; Hartman, Mikael; Ong, Kong Wee; Tan, Benita K T; Rozen, Steven G; Tan, Patrick; Tan, Puay Hoon; Teh, Bin Tean

    2015-11-01

    Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications. PMID:26437033

  1. Breast reconstruction following excision of phylloides tumor.

    PubMed

    Lai, Y L; Weng, C J; Noordhoff, M S

    1999-08-01

    There are few papers published on breast reconstruction after excision of phylloides tumor. Six patients who had reconstruction of the breast following excision of phylloides tumor are described. All underwent wide excision or subcutaneous mastectomy followed by immediate or delayed reconstruction with implants or autologous tissue. The mean follow-up was 5 years (range, 2.5-7 years). One patient died of metastases; the others survived without evidence of recurrence. The etiology, incidence, diagnosis, and treatment of these tumors are discussed. The aesthetic results in these patients is also described. PMID:10454317

  2. 17β-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line.

    PubMed

    Heger, Zbynek; Gumulec, Jaromir; Cernei, Natalia; Tmejova, Katerina; Kopel, Pavel; Balvan, Jan; Masarik, Michal; Zitka, Ondrej; Beklova, Miroslava; Adam, Vojtech; Kizek, Rene

    2015-02-01

    The present study suggests and describes the application of a delivery system for antisense oligonucleotides against mRNA encoding estrogen receptor proteins α and β. The delivery system is composed of a cationic liposome envelope containing 17β-estradiol (E2) in its structure. Cationic liposomes protect cargo against the extracellular matrix, and E2 can increase its shuttling efficiency into cells. Using MCF-7 cells derived from estrogen receptor-positive ductal carcinoma, treatment with liposomes against ERα was found to decrease MCF-7 proliferation, and importantly the application of both the antisense against ERα and β exhibited an antiproliferative effect expressed as cell viability. Using qRT-PCR, it was shown that MT1A, NF-κB1 and K-ras genes, but not TFF1, were downregulated using E2-based liposomes (evaluated at P=0.05). Further indicators of oxidative stress were employed to assess the effect on treatment efficiency. Glutathione (GSH/GSSG redox ratio), metallothionein (MT) and malondialdehyde (MDA) confirmed a positive effect of antisense therapy resulting in their decreased levels in the MCF-7 cells. Based on these data, we suggest that E2-based liposomes offer sufficient transfer efficiency and moreover, due to the effect on NF-κB1, MT and GSH, tumor cells can be chemosensitized to increase treatment effectiveness. PMID:25434399

  3. Computer assisted biopsy of breast tumors.

    PubMed

    Arambula Cosio, Fernando; Lira Berra, Eric; Hevia Montiel, Nidiyare; Garcia Segundo, Cresencio; Garduno, Edgar; Alvarado Gonzalez, Montserrat; Quispe Siccha, Rosa Ma; Reyes Ramirez, Bartolome; Hazan Lasri, Eric

    2010-01-01

    In this paper we report our preliminary results of the development of a computer assisted system for breast biopsy. The system is based on tracked ultrasound images of the breast. A three dimensional ultrasound volume is constructed from a set of tracked B-scan images acquired with a calibrated probe. The system has been designed to assist a radiologist during breast biopsy, and also as a training system for radiology residents. A semiautomatic classification algorithm was implemented to assist the user with the annotation of the tumor on an ultrasound volume. We report the development of the system prototype, tested on a physical phantom of a breast with a tumor, made of polivinil alcohol. PMID:21097108

  4. Phyllodes Tumor in a Lactating Breast

    PubMed Central

    Murthy, Sudha S.; Raju, K. V. V. N.; Nair, Haripreetha G.

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  5. Phyllodes Tumor in a Lactating Breast.

    PubMed

    Murthy, Sudha S; Raju, K V V N; Nair, Haripreetha G

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  6. Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An estimated 70% of breast cancer tumors utilize estrogen receptor (ER) signaling to maintain tumorigenesis, and targeting of the estrogen receptor is a common method of treatment for these tumor types. However, ER-positive (+) breast cancers often acquire drug resistant or altered ER activity in r...

  7. Comprehensive molecular portraits of human breast tumors

    PubMed Central

    2012-01-01

    Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer. PMID:23000897

  8. Unusual Benign Tumors of the Breast

    PubMed Central

    Adrada, Beatriz E; Krishnamurthy, Savitri; Carkaci, Selin; Posleman-Monetto, Flavia E; Ewere, Adesuwa; Whitman, Gary J

    2015-01-01

    The purpose of this article is to describe the imaging characteristics of a variety of benign breast tumors that may be encountered in daily practice, in order to formulate an appropriate differential diagnosis and to establish concordance between the imaging and the pathologic findings, and to assist the clinician with appropriate management. PMID:26085959

  9. Breast cancer intra-tumor heterogeneity

    PubMed Central

    2014-01-01

    In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic. PMID:25928070

  10. HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation

    SciTech Connect

    Han, Wen; Jones, Frank E.

    2014-01-10

    unaffected by loss of HER4 expression. In summary, we demonstrate for the first time that a cell surface receptor functions as an obligate ER coactivator with functional specificity associated with breast tumor cell proliferation and cell cycle progression. Nearly 90% of ER positive tumors coexpress HER4, therefore we predict that the majority of breast cancer patients would benefit from a strategy to therapeutic disengage ER/4ICD coregulated tumor cell proliferation.

  11. Anandamide inhibits breast tumor-induced angiogenesis

    PubMed Central

    Picardi, P; Ciaglia, E; Proto, MC; Pisanti, S

    2014-01-01

    Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death in women. Great advances in the treatment of primary tumors have led to a significant increment in the overall survival rates, however recurrence and metastatic disease, the underlying cause of death, are still a medical challenge. Breast cancer is highly dependent on neovascularization to progress. In the last years several anti-angiogenic drugs have been developed and administered to patients in combination with chemotherapeutic drugs. Collected preclinical evidence has proposed the endocannabinoid system as a potential target in cancer. The endocannabinoid anandamide has been reported to affect breast cancer growth at multiple levels, by inhibiting proliferation, migration and invasiveness in vitro and in vivo and by directly inhibiting angiogenesis. Aim of the present work is to investigate if anandamide is able to affect the proangiogenic phenotype of the highly invasive and metastatic breast cancer cells MDA-MB-231. We found that following anandamide treatment, MDAMB-231 cells lose their ability to stimulate endothelial cells proliferation in vitro, due to a significant inhibition of all the pro-angiogenic factors produced by these cells. This finding adds another piece of evidence to the anti-tumor efficacy of anandamide in breast cancer. PMID:25147760

  12. Circulating Tumor Cells in Breast Cancer Patients.

    PubMed

    Hall, Carolyn; Valad, Lily; Lucci, Anthony

    2016-01-01

    Breast cancer is the most commonly diagnosed cancer among women, resulting in an estimated 40,000 deaths in 2014.1 Metastasis, a complex, multi-step process, remains the primary cause of death for these patients. Although the mechanisms involved in metastasis have not been fully elucidated, considerable evidence suggests that metastatic spread is mediated by rare cells within the heterogeneous primary tumor that acquire the ability to invade into the bloodstream. In the bloodstream, they can travel to distant sites, sometimes remaining undetected and in a quiescent state for an extended period of time before they establish distant metastases in the bone, lung, liver, or brain. These occult micrometastatic cells (circulating tumor cells, CTCs) are rare, yet their prognostic significance has been demonstrated in both metastatic and non-metastatic breast cancer patients. Because repeated tumor tissue collection is typically not feasible and peripheral blood draws are minimally invasive, serial CTC enumeration might provide "real-time liquid biopsy" snapshots that could be used to identify early-stage breast cancer patients with micrometastatic disease who are at risk for disease progression and monitor treatment response in patients with advanced disease. In addition, characterizing CTCs might aid in the development of novel, personalized therapies aimed at eliminating micrometastases. This review describes current CTC isolation, detection, and characterization strategies in operable breast cancer. PMID:27481009

  13. Breast tumor metastasis: analysis via proteomic profiling

    PubMed Central

    Goodison, Steve; Urquidi, Virginia

    2012-01-01

    The ability to predict the metastatic behavior of a patient’s cancer, as well as to detect and eradicate such recurrences, remain major clinical challenges in oncology. While many potential molecular biomarkers have been identified and tested previously, none have greatly improved the accuracy of specimen evaluation over routine histopathological criteria and, to date, they predict individual outcomes poorly. The ongoing development of high-throughput proteomic profiling technologies is opening new avenues for the investigation of cancer and, through application in tissue-based studies and animal models, will facilitate the identification of molecular signatures that are associated with breast tumor cell phenotype. The appropriate use of these approaches has the potential to provide efficient biomarkers, and to improve our knowledge of tumor biology. This, in turn, will enable the development of targeted therapeutics aimed at ameliorating the lethal dissemination of breast cancer. In this review, we focus on the accumulating proteomic signatures of breast tumor progression, particularly those that correlate with the occurrence of distant metastases, and discuss some of the expected future developments in the field. PMID:18532913

  14. Molecular biology of breast tumors and prognosis

    PubMed Central

    Baldassarre, Gustavo; Belletti, Barbara

    2016-01-01

    Breast cancer is the most common cancer among women worldwide. Great scientific, economical, and organizational efforts are in place to understand the causes of onset, identify the critical molecular players of progression, and define new lines of intervention providing more benefits and less toxicity. These efforts have certainly not been vain, since overall survival, especially in specific subsets of breast cancer, has greatly improved during the last decades. At present, breast cancer patients’ treatment and care have reached a high standard of quality, and currently one of the most urgent needs resides in the necessity to better distinguish the tumors that need to be more aggressively treated and identify the best therapeutic option tailored to each patient. This objective will be achievable only if the information clarifying the biology of breast cancer can be successfully transferred to the clinic. A common effort by scientists and clinicians toward this integration and toward the use of multidisciplinary approaches will be necessary to reach this important goal. PMID:27134741

  15. Tumoral pseudoangiomatous stromal hyperplasia of the breast.

    PubMed

    Wieman, Stephanie M; Landercasper, Jeffrey; Johnson, Jeanne M; Ellis, Richard L; Wester, Susan M; Lambert, Pamela J; Ross, Lauren A

    2008-12-01

    Tumoral pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferative disease of the breast. The majority of the literature reports of PASH have not contained detailed descriptions of the imaging characteristics of PASH. A 10-year retrospective study of patients with tumoral PASH and a 20-year Ovid MEDLINE search were performed to determine whether specific imaging and needle biopsy results could characterize PASH preoperatively. We identified 22 patients with tumoral PASH. Seventeen (77%) of 22 women had a palpable lump and 14 (72%) of 21 had a density on mammography. Ultrasound (US) findings included mixed or hypoechoic echogenicity in 83 per cent and ill-defined borders in 62 per cent. Eight (36%) patients had lesions with a Breast Imaging Reporting and Data System (BI-RADS) classification of 4 or 5. The sensitivity of preoperative core needle biopsy (CNB) to identify PASH was 83 per cent. A review of the literature revealed that 90 per cent of patients with PASH had some malignant imaging characteristics and 95 per cent had a mass on mammography. The imaging characteristics of PASH exhibited marked variability. Excision of PASH after CNB may be considered for patients with symptoms, enlarging lesions, or lesions classified as BI-RADS 4 or 5. PASH diagnosed by CNB allows selected patients to avoid excision. PMID:19097540

  16. The perivascular niche regulates breast tumor dormancy

    PubMed Central

    Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R.; Evason, Kimberley J.; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A.; Stainier, Didier Y.R.; Chen, Emily I.; Lyden, David

    2013-01-01

    In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what ‘wakes them up’, are fundamental problems in tumor biology. To address these questions, we utilized metastasis assays in mice to show that dormant DTCs reside upon microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumor-promoting, endothelial tip cell-derived factors. Our work reveals that stable microvasculature constitutes a ‘dormant niche,’ whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425

  17. Breast Cancer Proteomics – Differences in Protein Expression between Estrogen Receptor-Positive and -Negative Tumors Identified by Tandem Mass Tag Technology

    PubMed Central

    Ruckhäberle, Eugen; Karn, Thomas; Hanker, Lars; Schwarz, Josef; Schulz-Knappe, Peter; Kuhn, Karsten; Böhm, Gitte; Selzer, Stefan; Erhard, Neukum; Engels, Knut; Holtrich, Uwe; Kaufmann, Manfred; Rody, Achim

    2010-01-01

    Background Proteomic analysis has become an effective tool in breast cancer research. In this study, we applied the new gel-free tandem mass tag (TMT) reference method for the first time in breast cancer. Materials and Methods Proteomic analysis was used to compare 10 estrogen receptor (ER)-positive and 10 ER-negative samples. The results of the proteomic approach were validated by Western blot, immunohistochemistry and gene expression analysis. Results 17 proteins with significant differences in expression were identified. 13 proteins were overexpressed in ER-negative tumors and 4 were overexpressed in ER-positive samples. All these proteins were characterized by relatively high cellular abundance. Conclusions Our results demonstrate that the gel-free TMT approach allows the quantification of differences in protein expression levels. Further improvement of the sensitivity by subfractionation of the tissue should allow also the identification of low-abundance proteins and might lead to the use of this method in breast cancer research. PMID:22619634

  18. Tumor biology in estrogen receptor-positive, human epidermal growth factor receptor type 2-negative breast cancer: Mind the menopausal status

    PubMed Central

    Yamashita, Hiroko

    2015-01-01

    Breast cancer is not one disease, but can be categorized into four major molecular subtypes according to hormone receptor [estrogen receptor (ER) and progesterone receptor (PgR)] and human epidermal growth factor receptor type 2 (HER2) expression status. Ki67 labeling index and/or multigene assays are used to classify ER-positive, HER2-negative breast cancer into luminal A and luminal B (HER2-negative) subtypes. To date, most studies analyzing predictive or prognostic factors in ER-positive breast cancer have been performed in postmenopausal women, mainly using patients and samples in adjuvant aromatase inhibitor trials. In contrast, even the clinical roles of PgR and Ki67 have been little analyzed so far in premenopausal women. PgR is one of the estrogen-responsive genes, and it has been reported that plasma estradiol levels are related to expression levels of estrogen-responsive genes including PGR in ER-positive breast cancer. In this article, biological differences, especially differences in expression of PgR and Ki67 in ER-positive breast cancer between pre- and postmenopausal women are discussed. Clinical roles of PgR and Ki67 in ER-positive breast cancer differ between pre- and postmenopausal women. We suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status. PMID:26677435

  19. Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor of breast

    PubMed Central

    Srivastava, Smita; Arora, Jyoti; Parakh, Anushri; Goel, Ruchika Kumar

    2016-01-01

    Extraskeletal Ewing's sarcoma (EES) is a rare soft tissue tumor that is morphologically indistinguishable from skeletal ES. We report a case of a 25-year-old female with recurrent EES/primitive neuroectodermal tumor of right breast with imaging findings on mammogram, ultrasound, magnetic resonance imaging breast, and positron emission tomography–computed tomography. PMID:27413270

  20. An Unusual Tumor of the Breast - Extraskeletal Ewing Sarcoma

    PubMed Central

    TAŞLI, FUNDA; ÖZKÖK, GÜLIZ; AYKAS, AHMET; POSTACI, HAKAN; USLU, ADAM

    2014-01-01

    Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor presenting as a breast mass is uncommon. It may pose a diagnostic challenge. In order to increase awareness and identify potential diagnostic pitfalls, we report a 24 year-old woman extraosseous Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor arising in the breast. PMID:24791212

  1. Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

    ClinicalTrials.gov

    2016-01-12

    Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

  2. Clinical and cytopathological aspects in phyllodes tumors of the breast.

    PubMed

    Pătraşcu, Anca; Popescu, Carmen Florina; Pleşea, I E; Bădulescu, Adriana; Tănase, Florentina; Mateescu, Garofiţa

    2009-01-01

    The frequency of mesenchymal breast tumors is very low, being represented mostly by tumors with biphasic proliferation (phyllodes tumors) and less by other types of non-epithelial tumors. From clinical point of view, phyllodes tumors (PT) can mimic a breast carcinoma. Therefore, the preoperative diagnosis by cytological examination on material obtained by fine needle aspiration (FNA) is very important for adequate treatment of these tumors. In current study, we assessed clinical aspects of 79 phyllodes tumors regarding patient's age and localization of the tumors. In 17 out of 79 cases, it has been performed FNA within the tumors with further cytological examination on the smears obtained. The median age of the patients was 46.07-year-old, being progressively higher with grade of the tumors with significant values between benign and borderline tumors (p=0.04954) and between benign and malignant ones (p=0.02890). The distinguish on the smears of stromal fragments and naked stromal nuclei with variable grade of atypia regarding the tumoral type, in detriment of epithelial elements have been conclusive for fibroepithelial lesion as cytopathological diagnosis. The preoperative differentiation between a breast phyllodes tumor and a breast carcinoma is extremely important for avoiding of a useless radical surgery for the patient. If the fine needle aspiration was correctly performed, the accuracy of the cytodiagnosis has been 82% in current study. PMID:19942954

  3. Huge malignant phyllodes breast tumor: a real entity in a new era of early breast cancer.

    PubMed

    Testori, Alberto; Meroni, Stefano; Errico, Valentina; Travaglini, Roberto; Voulaz, Emanuele; Alloisio, Marco

    2015-01-01

    Phyllodes tumor is an extremely rare tumor of the breast. It occurs in females in the third and fourth decades. The difficulty in distinguishing between phyllodes tumors and benign fibroadenoma may lead to misdiagnosis. Lymph node involvement is rarely described in phyllodes tumors; for this reason, sentinel node biopsy may be warranted. We present a case of a 33-year-old woman affected by huge tumor of the right breast with ulceration in the skin with a rapid tumor growth and with omolateral axillary metastasis. PMID:25880837

  4. [Research progress of tumor infiltrating lymphocytes in breast cancer].

    PubMed

    Huang, Jiahui; Chen, Xiaosong; Shen, Kunwei

    2015-09-01

    Breast cancer is a heterogeneous disease. The formation and progression of tumor and the sensitivity to treatment differs from patient to patient. In addition to the widely used molecular subtype, novel markers are needed to better personalize the treatment of breast cancer. Tumor infiltrating lymphocyte (TIL) have been consistently documented in breast cancer lesions especially in triple negative and human epidermal growth factor receptor-2 positive breast cancer. Several clinical trials have revealed that TIL are associated with prognosis and can predict therapeutic efficacy of special therapy. TIL could be divided to different subtypes including CD8 + TIL, CD4 + TIL, cytotoxic T lymphocyte-associated antigen-4 + TIL, programmed death-1 + TIL. They play different roles in the process of anti-tumor immunity and can predict different prognosis. Screening out special TIL subtype which is well associated with prognosis and therapeutic efficacy and developing targeting immunotherapy can help to improve outcomes of breast cancer patients. PMID:26654152

  5. Bilateral desmoid tumor of the breast: case seriesand literature review

    PubMed Central

    Wongmaneerung, Phanchaporn; Somwangprasert, Areewan; Watcharachan, Kirati; Ditsatham, Chagkrit

    2016-01-01

    Background Desmoid tumor of the breast is very rare and locally aggressive but has no distant metastasis. Bilateral lesions are extremely rare, found in only 4% of patients. Two cases of bilateral desmoid tumor of the breast are reported. The clinical presentation, diagnosis, imaging, treatment, and follow-up outcomes of recurrence as well as a brief literature review are provided. Case reports Case 1 is a 31-year-old woman who presented with nipple retraction. An ultrasound revealed BIRAD V in both breasts. She underwent a bilateral excisional biopsy under ultrasound mark with the pathology result of extra-abdominal desmoid tumor in both breasts. The patient had a bilateral mastectomy with silicone implantation due to the involved margins by excision. She remained tumor free after 7-year follow-up. Case 2 is a 28-year-old woman who presented with a lump on her right breast that she had discovered ~2 months earlier. An ultrasound showed a spiculated mass in the right breast and some circumscribed hypoechoic masses in both breasts. A bilateral breast excision was done. The pathology result was an extra-abdominal desmoid tumor. She had recurrence on both sides and underwent a mastectomy and silicone implantation. The tumor has not recurred after 1-year follow-up. Conclusion Imaging cannot distinguish between benign breast lesions and malignancy. Pathology results are helpful in making a definitive diagnosis. Given that the desmoid tumor is locally aggressive, a local excision with clear margins is recommended. Chemotherapy and hormonal treatment are controversial. PMID:27578999

  6. Extremely rare borderline phyllodes tumor in the male breast: a case report.

    PubMed

    Kim, Jung Gyu; Kim, Shin Young; Jung, Hae Yoen; Lee, Deuk Young; Lee, Jong Eun

    2015-01-01

    Phyllodes tumor of the male breast is an extremely rare disease, and far fewer cases of borderline phyllodes tumors than benign or malignant tumors in the male breast have been reported. We report a case of borderline phyllodes tumor in the male breast with imaging findings of the tumor and pathologic correlation. PMID:26316459

  7. Pigmented papillary carcinoma: a rare tumor of the male breast.

    PubMed

    Farkas, Andrea; Istók, Roland; Székely, Eszter; Glasz, Tibor; Kulka, Janina

    2008-09-01

    Primary melanin pigment containing tumors of the breast are rare. We report a pigmented papillary carcinoma of a 60-year-old male patient who presented a firm mass 1.7 cm in diameter with an ill defined border on ultrasonography behind the mamilla. To the best of our knowledge this is the third case report of this type of tumor in male breast. PMID:18575825

  8. Coexistence of malignant phyllodes tumor and her2-positive locally advanced breast cancer in distinct breasts: A case report

    PubMed Central

    Sato, Tomoi; Muto, Ichiro; Sakai, Takeshi

    2016-01-01

    Introduction Phyllodes tumor of the breast is a rare biphasic neoplasm, accounting for less than 1% of all breast tumors. Coexistence of phyllodes tumor and breast cancer in distinct breasts is extremely rare. Case presentation A 47-year-old Japanese woman presented with bilateral breast lumps. A HER2-positive, unresectable invasive carcinoma in the right breast and fibroadenoma in the left were diagnosed via core needle biopsy. During chemotherapy with anti-HER2 therapy, the breast cancer shrank quickly, while the left breast lump suddenly enlarged. Under a diagnosis of malignant neoplasm of the breast, left mastectomy was performed. Malignant phyllodes tumor was diagnosed by postoperative histological examination and recurred in multiple areas as early as 2 months after surgery. Discussion Only 10 cases of coexisting phyllodes tumor and breast cancer in distinct breasts have been reported in the English literature. Phyllodes tumor associated with breast cancer in distinct breasts tends to be malignant. This is the first case of phyllodes tumor rapidly enlarging during anti-HER2 chemotherapy for locally advanced HER2-positive breast cancer. Conclusion Even during effective treatment of advanced or recurrent breast cancer, attention should also be paid to the contralateral breast for the possible association of a second malignancy such as phyllodes tumor. PMID:26773878

  9. Recurrent angio-fibroma of breast masquerading as phyllodes tumor.

    PubMed

    Chaurasia, Jai K; Alam, Feroz; Shadan, Mariam; Naim, Mohammed

    2015-01-01

    A young Indian female presented with a recurring tumor in the right breast masquerading as phyllodes tumor. Patient had history of five times excision and recurrences of the tumor, diagnosed as fibrous phyllodes of the breast. Presently, a well-circumscribed tumor of about 10 cm size, comprising of benign fibrous-angiomatous tissue with evidence of foci of pyogenic vasculitis was observed. Immuno-histochemical markers for the myo-epithelial and epithelial elements excluded the possibility of fibrous phyllodes, inflammatory myofibroblastic tumor, desmoid fibromatosis, and metaplastic carcinoma. The present findings were diagnostic of an inflammatory angio-fibroma of the right breast, not reported in the earlier literature. The observations indicated that the female breast may be susceptible to spontaneous productive and common-antibiotic-resistant focal septic vascular inflammation giving rise to angio-fibromatous proliferation producing a well-defined tumor mass in the breast, distinguishable from the other breast lesions by the connective tissue stains and immuno-histochemical markers. PMID:26458623

  10. Occult breast tumor reservoir: biological properties and clinical significance.

    PubMed

    Santen, Richard J; Yue, Wei; Heitjan, Daniel F

    2013-08-01

    Small, occult, undiagnosed breast cancers are found at autopsy in up to 15.6 % of women dying from unrelated causes with an average of 7 % from eight separate studies. The mammographic detection threshold of breast tumors ranges from 0.88 to 1.66 cm in diameter based on the patient's age. Tumor growth rates, expressed as "effective doubling times," vary from 10 to >700 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. Our models facilitate interpretation of the Women's Health Initiative (WHI) and antiestrogen breast cancer prevention studies. A nude mouse xenograft model was used to validate our assumption that breast tumors grow in a log-linear fashion. We then used our previously reported occult tumor growth (OTG) and computer-simulated tumor growth models to analyze various clinical trial data. Parameters used in the OTG model included a 200-day effective doubling time, 7 % prevalence of occult tumors, and 1.16 cm detection threshold. These models had been validated by comparing predicted with observed incidence of breast cancer in eight different populations of women. Our model suggests that menopausal hormone therapy with estrogens plus a progestogen (E + P) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. We provide a potential explanation for the lack of an increase in breast cancer incidence in the subgroup of women in the WHI who had not received E + P prior to randomization. This result may have reflected a leftward skew in the distribution of occult tumor doublings and insufficient time for stimulated tumors to reach the detection threshold. Our model predicted that estrogen alone reduced the incidence of breast cancer as a result of apoptosis. Understanding of the biology of occult tumors suggests that breast cancer "prevention" with antiestrogens or aromatase

  11. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  12. Relevance of tumor-infiltrating lymphocytes in breast cancer.

    PubMed

    Dushyanthen, Sathana; Beavis, Paul A; Savas, Peter; Teo, Zhi Ling; Zhou, Chenhao; Mansour, Mariam; Darcy, Phillip K; Loi, Sherene

    2015-01-01

    While breast cancer has not been considered a cancer amenable to immunotherapeutic approaches, recent studies have demonstrated evidence of significant immune cell infiltration via tumor-infiltrating lymphocytes in a subset of patient tumors. In this review we present the current evidence highlighting the clinical relevance and utility of tumor-infiltrating lymphocytes in breast cancer. Retrospective and prospective studies have shown that the presence of tumor-infiltrating lymphocytes is a prognostic marker for higher responses to neoadjuvant chemotherapy and better survival, particularly in triple negative and HER2-positive early breast cancer. Further work is required to determine the immune subsets important in this response and to discover ways of encouraging immune infiltrate in tumor-infiltrating lymphocytes-negative patients. PMID:26300242

  13. Expression of TGF-beta signaling factors in invasive breast cancers: relationships with age at diagnosis and tumor characteristics.

    PubMed

    Figueroa, Jonine D; Flanders, Kathleen C; Garcia-Closas, Montserrat; Anderson, William F; Yang, Xiaohong R; Matsuno, Rayna K; Duggan, Máire A; Pfeiffer, Ruth M; Ooshima, Akira; Cornelison, Robert; Gierach, Gretchen L; Brinton, Louise A; Lissowska, Jolanta; Peplonska, Beata; Wakefield, Lalage M; Sherman, Mark E

    2010-06-01

    The transforming growth factor beta (TGF-beta) pathway can play either a tumor-suppressing or a tumor-promoting role in human breast carcinogenesis. In order to determine whether expression of TGF-beta signaling factors varies by age at onset and breast tumor characteristics that have prognostic significance, we undertook a study of 623 women with invasive breast carcinoma enrolled in a population-based case-control study conducted in Poland from 2000 to 2003. TGF-beta signaling factors were analyzed by immunohistochemistry in tumor tissue microarrays. We found that most tumors expressed extracellular-TGF-beta1 (78%), TGF-beta2 (91%), TGF-beta3 (93%), TGF-betaR2 (72%), and phospho-SMAD2 (61%), whereas intracellular-TGF-beta1 was expressed in 32% of tumors. Expression of TGF-beta ligands (beta1, beta2, and beta3) was associated with prognostically favorable pathological features including small size, and low grade, and these associations were similar for ER-positive and negative tumors. On the contrary, expression of the receptor TGF-betaR2 was primarily associated with small tumor size among ER-negative tumors, while expression of the transcription factor phospho-SMAD2 was associated with positive nodal status among ER-negative tumors. The greater frequency of expression of phospho-SMAD2 in cancers associated with lymph node metastases is consistent with a pro-progression role for TGF-beta. In addition, expression of extracellular-TGF-beta1 (P = 0.005), TGF-betaR2 (P = 8.2E-11), and phospho-SMAD2 (P = 1.3E-8) was strongly associated with earlier age at onset, independent of ER status. Our data provide evidence that TGF-beta signaling patterns vary by age and pathologic features of prognostic significance including ER expression. These results warrant analysis in studies of clinical outcomes accounting for age, ER status and treatment. PMID:19937272

  14. Expression of TGF-β signaling factors in invasive breast cancers: relationships with age at diagnosis and tumor characteristics

    PubMed Central

    Flanders, Kathleen C.; Garcia-Closas, Montserrat; Anderson, William F.; Yang, Xiaohong R.; Matsuno, Rayna K.; Duggan, Máire A.; Pfeiffer, Ruth M.; Ooshima, Akira; Cornelison, Robert; Gierach, Gretchen L.; Brinton, Louise A.; Lissowska, Jolanta; Peplonska, Beata; Wakefield, Lalage M.; Sherman, Mark E.

    2014-01-01

    The transforming growth factor beta (TGF-β) pathway can play either a tumor-suppressing or a tumor-promoting role in human breast carcinogenesis. In order to determine whether expression of TGF-β signaling factors varies by age at onset and breast tumor characteristics that have prognostic significance, we undertook a study of 623 women with invasive breast carcinoma enrolled in a population-based case–control study conducted in Poland from 2000 to 2003. TGF-β signaling factors were analyzed by immunohistochemistry in tumor tissue microarrays. We found that most tumors expressed extracellular-TGF-β1 (78%), TGF-β2 (91%), TGF-β3 (93%), TGF-βR2 (72%), and phospho-SMAD2 (61%), whereas intracellular-TGF-β1 was expressed in 32% of tumors. Expression of TGF-β ligands (β1, β2, and β3) was associated with prognostically favorable pathological features including small size, and low grade, and these associations were similar for ER-positive and negative tumors. On the contrary, expression of the receptor TGF-βR2 was primarily associated with small tumor size among ER-negative tumors, while expression of the transcription factor phospho-SMAD2 was associated with positive nodal status among ER-negative tumors. The greater frequency of expression of phospho-SMAD2 in cancers associated with lymph node metastases is consistent with a pro-progression role for TGF-β. In addition, expression of extracellular-TGF-β1 (P = 0.005), TGF-βR2 (P = 8.2E-11), and phospho-SMAD2 (P = 1.3E-8) was strongly associated with earlier age at onset, independent of ER status. Our data provide evidence that TGF-β signaling patterns vary by age and pathologic features of prognostic significance including ER expression. These results warrant analysis in studies of clinical outcomes accounting for age, ER status and treatment. PMID:19937272

  15. Optically measured microvascular blood flow contrast of malignant breast tumors.

    PubMed

    Choe, Regine; Putt, Mary E; Carlile, Peter M; Durduran, Turgut; Giammarco, Joseph M; Busch, David R; Jung, Ki Won; Czerniecki, Brian J; Tchou, Julia; Feldman, Michael D; Mies, Carolyn; Rosen, Mark A; Schnall, Mitchell D; DeMichele, Angela; Yodh, Arjun G

    2014-01-01

    Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92-2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94-2.66), and using normal tissue in the contralateral breast was 2.27 (1.90-2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography. PMID:24967878

  16. Cancer-associated adipocytes promotes breast tumor radioresistance

    SciTech Connect

    Bochet, Ludivine; Meulle, Aline; Imbert, Sandrine; Salles, Bernard; Valet, Philippe; Muller, Catherine

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  17. How to approach phyllodes tumors of the breast?

    PubMed Central

    Acar, Turan; Tarcan, Ercüment; Hacıyanlı, Mehmet; Kamer, Erdinç; Peşkersoy, Mustafa; Yiğit, Seyran; Gür, Özlem; Cin, Necat; Sarı, Ayşegül Akder; Tatar, Fatma

    2015-01-01

    Objective: Phyllodes tumor of the breast is a rare fibroepithelial breast tumor that comprise 0.3–0.9% of primary breast neoplasms. In this study, we aimed to present clinicopathologic symptoms of our patients along with their treatment modality. Material and Methods: Clinicopathologic properties and treatment modality of 20 phyllodes tumor patients who underwent surgery between January 2008 and January 2013 were retrospectively evaluated. Results: Median patient age was 47 years (22–75). Fine-needle aspiration biopsy was applied to 19 patients. Biopsy results were reported as suspicious in four, malignant in three, benign in 11, and as non-diagnostic in one patient. Final histopathology reports revealed two benign, one malignant and one borderline tumor out of the four patients with suspicious findings on fine needle aspiration biopsy; all patients with malignant cytology had malignancy. There were two borderline and nine benign lesions within the benign biopsy group. Sixteen patients underwent segmental mastectomy, four patients underwent mastectomy with/without axillary dissection. The median tumor size was 6 (1–13) cm. Histopathologically, 11 (55%) tumors were benign, 5 (25%) were borderline, and 4 (20%) were malignant. Two of the four patients with malignancy underwent radiotherapy and chemotherapy, and one patient only received chemotherapy as adjuvant treatment. Conclusion: Phyllodes tumors are rare, mix-type breast tumors. Due to high rates of local recurrence and potential for malignancy, preoperative diagnosis and accurate management are important. PMID:26668526

  18. Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

    PubMed

    Wallace, Julie A; Li, Fu; Balakrishnan, Subhasree; Cantemir-Stone, Carmen Z; Pecot, Thierry; Martin, Chelsea; Kladney, Raleigh D; Sharma, Sudarshana M; Trimboli, Anthony J; Fernandez, Soledad A; Yu, Lianbo; Rosol, Thomas J; Stromberg, Paul C; Lesurf, Robert; Hallett, Michael; Park, Morag; Leone, Gustavo; Ostrowski, Michael C

    2013-01-01

    Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies. PMID:23977064

  19. APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

    PubMed

    García-Castro, Araceli; Zonca, Manuela; Florindo-Pinheiro, Douglas; Carvalho-Pinto, Carla E; Cordero, Alex; Gutiérrez del Fernando, Burgo; García-Grande, Aránzazu; Mañes, Santos; Hahne, Michael; González-Suárez, Eva; Planelles, Lourdes

    2015-05-01

    APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy. PMID:25750171

  20. Modeling Breast Tumor Development with a Humanized Mouse Model.

    PubMed

    Arendt, Lisa M

    2016-01-01

    The tumor microenvironment plays a critical role in breast cancer growth and progression to metastasis. Here, we describe a method to examine stromal-epithelial interactions during tumor formation and progression utilizing human-derived mammary epithelial cells and breast stromal cells. This method outlines the isolation of each cell type from reduction mammoplasty tissue, the culture and genetic modification of both epithelial and stromal cells using lentiviral technology, and the method of humanizing and implantation of transformed epithelial cells into the cleared mammary fat pads of immunocompromised mice. This model system may be a useful tool to dissect signaling interactions that contribute to invasive tumor behavior and therapeutic resistance. PMID:27581027

  1. Phyllodes tumor of the breast metastasizing to the vulva.

    PubMed

    Ajenifuja, Olusegun Kayode; Kolomeyevskaya, Nonna; Habib, Fadi; Odunsi, Adekunle; Lele, Shashikant

    2015-01-01

    Phyllodes tumors of the breast are rare breast tumors that resemble fibroadenoma. They are composed of two types of tissues: stromal and glandular tissues. Unlike fibroadenoma, they are commonly found in the third decade of life and they tend to grow more rapidly. Depending on the relative components of the cells and mitotic activity, they are classified into benign, borderline, and malignant. They are usually present as a lump in the breast. Phyllodes tumors are usually managed by wide excision. The excision should be wide enough to ensure a tumor-free margin. Recurrence rate is very high and most recurrences are usually local. Metastasis to the vulva has not been reported. PMID:25960902

  2. Eosinophilic and granular cell tumors of the breast.

    PubMed

    Damiani, S; Dina, R; Eusebi, V

    1999-05-01

    Eosinophilic and granular cell tumors of the breast are a heterogeneous group encompassing both epithelial and mesenchymal lesions. A granular appearance of the cytoplasm may be caused by the accumulation of secretory granules, mitochondria, or lysosomes. In the breast, mucoid carcinomas, carcinomas showing apocrine differentiation, and neuroendocrine carcinomas are well known entities, while tumors with oncocytic and acinic cell differentiation have been only recently recognized. An abundance of lysosomes is characteristic of Schwannian granular cell neoplasms, but smooth muscle cell tumors also may have this cytoplasmic feature. Awareness of all these possibilities when granular cells are found in breast lesions improves diagnostic accuracy and helps to avoid misdiagnosis of both benign lesions and malignant tumors. PMID:10452577

  3. Unilateral synchronous breast tumors. Rare association of myofibroblastoma and osteosarcoma

    PubMed Central

    BARBUSCIA, M.A.; PAPARO, D.; QUERCI, A.; LEMMA, G.; FEDELE, F.; SCOLLICA, M.; CAIZZONE, A.; LENTINI, M.

    2013-01-01

    Summary: The authors describe the case of a patient with two particularly rare contiguous tumors, myofibroblastoma and osteosarcoma, in the same breast. Rare does not mean untreatable, and the chance of recovery is no less than with more common tumors. However, rare tumors do present a significant problem for pathologists due to diagnostic difficulties, and so an exact prognosis is not always possible. PMID:23660159

  4. Alignment of sources and detectors on breast surface for noncontact diffuse correlation tomography of breast tumors

    PubMed Central

    Huang, Chong; Lin, Yu; He, Lian; Irwin, Daniel; Szabunio, Margaret M.; Yu, Guoqiang

    2016-01-01

    Noncontact diffuse correlation tomography (ncDCT) is an emerging technology for 3D imaging of deep tissue blood flow distribution without distorting hemodynamic properties. To adapt the ncDCT for imaging in vivo breast tumors, we designed a motorized ncDCT probe to scan over the breast surface. A computer-aided design (CAD)-based approach was proposed to create solid volume mesh from arbitrary breast surface obtained by a commercial 3D camera. The sources and detectors of ncDCT were aligned on the breast surface through ray tracing to mimic the ncDCT scanning with CAD software. The generated breast volume mesh along with the boundary data of ncDCT at the aligned source and detector pairs were used for finite-element-method-based flow image reconstruction. We evaluated the accuracy of source alignments on mannequin and human breasts; largest alignment errors were less than 10% in both tangential and radial directions of scanning. The impact of alignment errors (assigned 10%) on the tumor reconstruction was estimated using computer simulations. The deviations of simulated tumor location and blood flow contrast resulted from the alignment errors were 0.77 mm (less than the node distance of 1 mm) and 1%, respectively, which result in minor impact on flow image reconstruction. Finally, a case study on a human breast tumor was conducted and a tumor-to-normal flow contrast was reconstructed, demonstrating the feasibility of ncDCT in clinical application. PMID:26479823

  5. Working formulation of neuroendocrine tumors of the skin and breast.

    PubMed

    Asioli, Sofia; Foschini, Maria Pia; Masetti, Riccardo; Eusebi, Vincenzo

    2014-06-01

    In the skin and breast, endocrine tumors are composed of a heterogeneous mixture of endocrine and exocrine cells. The definition of "pure" endocrine carcinomas is a matter for debate, and as a consequence, there is lack of uniform diagnostic criteria. There are no significant clinical differences in either overall or disease-free survival between matched neoplasms with endocrine and without endocrine differentiation nor between the degree of endocrine differentiation and tumor size, stage, or prevalence of vascular invasion for both sites (skin and breast). Here, endocrine tumors of the skin and breast are grouped respectively into three categories that include most of the neuroendocrine tumors of the skin and breast as seen in routine practice. It was felt that the number of different types of neuroendocrine tumors is so conspicuous that it is impossible to organize them in an orderly classification. It has been proposed therefore, for practical diagnostic routine purposes, to arrange these neoplasms into a working formulation. The latter includes heterogeneous lesions respectively of the skin and breast within the same group that have clinical features in common. PMID:24729037

  6. Molecular breast imaging: advantages and limitations of a scintimammographic technique in patients with small breast tumors.

    PubMed

    O'Connor, Michael K; Phillips, Stephen W; Hruska, Carrie B; Rhodes, Deborah J; Collins, Douglas A

    2007-01-01

    Preliminary studies from our laboratory showed that molecular breast imaging (MBI) can reliably detect tumors <2 cm in diameter. This study extends our work to a larger patient population and examines the technical factors that influence the ability of MBI to detect small breast tumors. Following injection of 740 MBq Tc-99m sestamibi, MBI was performed on 100 patients scheduled for biopsy of a lesion suspicious for malignancy that measured <2 cm on mammography or sonography. Using a small field of view gamma camera, patients were imaged in the standard mammographic views using light pain-free compression. Subjective discomfort, breast thickness, the amount of breast tissue in the detector field of view, and breast counts per unit area were measured and recorded. Follow-up was obtained in 99 patients; 53 patients had 67 malignant tumors confirmed at surgery. Of these, 57 of 67 were detected by MBI (sensitivity 85%). Sensitivity was 29%, 86%, and 97% for tumors <5, 6-10, and > or =11 mm in diameter, respectively. In seven patients, MBI identified eight additional mammographically occult tumors. Of 47 patients with no evidence of cancer at biopsy or surgery, there were 36 true negative and 11 false positive scans on MBI. MBI has potential for the regular detection of malignant breast tumors less than 2 cm in diameter. Work in progress to optimize the imaging parameters and technique may further improve sensitivity and specificity. PMID:17214787

  7. Rare Malignant Tumors of the Breast

    PubMed Central

    Miller, Trevor; Albarracin, Constance; Carkaci, Selin; Whitman, Gary J; Adrada, Beatriz E

    2015-01-01

    While the more common forms of breast cancer are well understood and recognized, there are many important rare malignancies that are less appreciated. Many of these cancers have imaging findings that, when understood, help to formulate a more educated differential diagnosis. In this article, the clinical features, imaging, and pathologic findings of rare breast malignancies will be discussed. PMID:26664775

  8. Preliminary observations of breast tumor collagen using synchrotron radiation

    NASA Astrophysics Data System (ADS)

    Lewis, Robert A.; Rogers, Keith D.; Hall, Christopher J.; Towns-Andrews, Elizabeth; Slawson, Susan; Evans, Andrew; Pinder, Sarah E.; Ellis, Ian O.; Boggis, Caroline R. M.; Hufton, Alan P.; Dance, David R.

    1999-10-01

    The most frequently occurring cancer in women is that of the breast where it accounts for almost 20% of all cancer deaths. The U.K. has the world's highest mortality rate from breast cancer with an increasing incidence of 25000 per annum. Characterizing the complex physiological and tissue changes that form the natural history of breast cancer is clearly important for understanding associated biological mechanisms and for diagnosis. We report the initial findings of a diffraction study of breast tissue collagen that we believe may be due to tumor genesis. Small angle, synchrotron X-ray scattering has enabled us to examine `core cut' biopsy specimens and characterize their collagen architecture. We present data that demonstrates possible structural differences between tumor and normal tissue. We discuss the implications of these findings in the context of using molecular structure characteristics as new and novel markers of disease progression.

  9. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy

    PubMed Central

    Williams, Carly Bess; Yeh, Elizabeth S; Soloff, Adam C

    2016-01-01

    Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality. PMID:26998515

  10. Racial variation in breast tumor promoter methylation in the Carolina Breast Cancer Study

    PubMed Central

    Conway, Kathleen; Edmiston, Sharon N.; Tse, Chiu-Kit; Bryant, Christopher; Kuan, Pei Fen; Hair, Brionna Y.; Parrish, Eloise A.; May, Ryan; Swift-Scanlan, Theresa

    2015-01-01

    Background African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes. Methods DNA methylation was evaluated at 1287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n=216) or non-AA (n=301) cases in the Carolina Breast Cancer Study. Results Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons (FDR), identified 7 CpG probes that showed significant (adjusted p<0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional 4 CpG probes differing by race within hormone receptor-negative (HR−) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3 and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBLs) from CBCS cases, indicating that these variations were not necessarily tumor-specific. Conclusions Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases. Impact Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. PMID:25809865

  11. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor

    PubMed Central

    Velez-Cubian, Frank O.; Gabordi, Robert C.; Smith, Prudence V.

    2016-01-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  12. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor.

    PubMed

    Velez-Cubian, Frank O; Gabordi, Robert C; Smith, Prudence V; Toloza, Eric M

    2016-06-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  13. Tumor-suppressor activity of RRIG1 in breast cancer

    PubMed Central

    2011-01-01

    Background Retinoid receptor-induced gene-1 (RRIG1) is a novel gene that has been lost in several types of human cancers. The aim of this study was to determine whether RRIG1 plays a role in breast cancer, such as in the suppression of breast cancer cell growth and invasion. Methods Immunohistochemistry was used to detect RRIG1 expression in breast tissue specimens. Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential. Reverse-transcription polymerase chain reaction and western blot assays were used to detect the changes in gene expression. The RhoA activation assay was used to assess RRIG1-induced inhibition of RhoA activity. Results The immunohistochemical data showed that RRIG1 expression was reduced in breast cancer tissues compared with normal and atypical hyperplastic breast tissues. RRIG1 expression was inversely correlated with lymph node metastasis of breast cancer but was not associated with the status of hormone receptors, such as estrogen receptor, progesterone receptor, or HER2. Furthermore, restoration of RRIG1 expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells. Expression of RRIG1 also reduced phosphorylated Erk1/2 and Akt levels; c-Jun, MMP9, and Akt expressions; and RhoA activity. In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential. Conclusion The data from the current study indicated that RRIG1 expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity. Future studies will determine the underlying molecular mechanisms and define RRIG1 as a tumor-suppressor gene in breast cancer. PMID:21266059

  14. Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers

    PubMed Central

    Parise, Carol A.

    2014-01-01

    Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification. PMID:24955090

  15. Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.

    PubMed

    Bolt, Alicia M; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  16. Tungsten Targets the Tumor Microenvironment to Enhance Breast Cancer Metastasis

    PubMed Central

    Bolt, Alicia M.; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M.; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K.

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients’ years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  17. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

    PubMed Central

    Kamdje, Armel Hervé Nwabo; Etet, Paul Faustin Seke; Vecchio, Lorella; Tagne, Richard Simo; Amvene, Jeremie Mbo; Muller, Jean-Marc; Krampera, Mauro; Lukong, Kiven Erique

    2014-01-01

    Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed. PMID:25516852

  18. Race-associated biological differences among Luminal A breast tumors.

    PubMed

    D'Arcy, Monica; Fleming, Jodie; Robinson, Whitney R; Kirk, Erin L; Perou, Charles M; Troester, Melissa A

    2015-07-01

    African-American (AA) women have higher breast cancer-specific mortality rates. A higher prevalence of the worse outcome Basal-like breast cancer subtype contributes to this, but AA women also have higher mortality even within the more favorable outcome Luminal A breast cancers. These differences may reflect treatment or health care access issues, inherent biological differences, or both. To identify potential biological differences by race among Luminal A breast cancers, gene expression data from 108 CAU and 57 AA breast tumors were analyzed. Race-associated genes were evaluated for associations with survival. Finally, expression of race- and survival-associated genes was evaluated in normal tissue of AA and CAU women. Six genes (ACOX2, MUC1, CRYBB2, PSPH, SQLE, TYMS) were differentially expressed by race among Luminal A breast cancers and were associated with survival (HR <0.8, HR >1.25). For all six genes, tumors in AA had higher expression of poor prognosis genes (CRYBB2, PSPH, SQLE, TYMS) and lower expression of good prognosis genes (ACOX2, MUC1). A score based on all six genes predicted survival in a large independent dataset (HR = 1.9 top vs. bottom quartile, 95% CI: 1.4-2.5). For four genes, normal tissue of AA and CAU women showed similar expression (ACOX2, MUC1, SQLE, TYMS); however, the poor outcome-associated genes CRYBB2 and PSPH were more highly expressed in AA versus CAU women's normal tissue. This analysis identified gene expression differences that may contribute to mortality disparities and suggests that among Luminal A breast tumors there are biological differences between AA and CAU patients. Some of these differences (CRYBB2 and PSPH) may exist from the earliest stages of tumor development, or may even precede malignancy. PMID:26109344

  19. Desmoid tumor occurring after reconstruction mammaplasty for breast carcinoma.

    PubMed

    Dale, P S; Wardlaw, J C; Wootton, D G; Resnick, J I; Giuliano, A E

    1995-11-01

    We present a case of desmoid tumor associated with prior alloplastic breast reconstruction. Wide local excision that includes chest wall resection, if necessary, is the primary treatment of choice. Patients with extensive nonresectable or recurrent disease may benefit from radiation therapy. Systemic therapy is a possibility in certain cases, but its toxicity generally precludes its use with this nonmetastatic tumor. Although this is the fourth reported case of desmoid tumor arising after implantation of a silicone prosthesis, we cannot claim a causal relationship. Careful follow-up consisting of yearly physical and mammagraphic examinations may facilitate early diagnosis and treatment of locally aggressive desmoid tumors but is not warranted, except in the context of routine screening for breast carcinoma. PMID:8579271

  20. A cyclized peptide derived from alpha fetoprotein inhibits the proliferation of ER-positive canine mammary cancer cells.

    PubMed

    Torres, Cristian Gabriel; Pino, Ana María; Sierralta, Walter Daniel

    2009-06-01

    The effects of estradiol (E2) and of an AFP-derived cyclized peptide (cP) on the proliferation of primary cultures of cancer cells isolated from spontaneous canine mammary tumors were studied. The cellular response to E2 and cP was related to the expression of estradiol receptor (isoforms alpha and beta). In ER-positive cells, 2 nM estradiol increased cell proliferation and the phosphorylation of ERK1/2; 2 microg/ml cP inhibited all these effects. Estradiol also increased HER2 immunoreactivity in ER-positive cells, an effect that was reverted to its basal values by cP. Estradiol stimulated in these cells the release of MMP2 and MMP9 and the shedding of HB-EGF, effects that the cP did not affect. ER-negative cells were refractory to estradiol or cP. All canine mammary tumor cells in culture responded to treatments analogously to human mammary cancer cells. Our results support the proposal of cP as a new, potentially effective therapeutic agent for the management of mammary cancer. PMID:19424616

  1. Stroma Cells in Tumor Microenvironment and Breast Cancer

    PubMed Central

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  2. Intraoperative Evaluation of Breast Tumor Margins with Optical Coherence Tomography

    PubMed Central

    Nguyen, Freddy T.; Zysk, Adam M.; Chaney, Eric J.; Kotynek, Jan G.; Oliphant, Uretz J.; Bellafiore, Frank J.; Rowland, Kendrith M.; Johnson, Patricia A.; Boppart, Stephen A.

    2009-01-01

    As breast cancer screening rates increase, smaller and more numerous lesions are being identified earlier, leading to more breast-conserving surgical procedures. Achieving a clean surgical margin represents a technical challenge with important clinical implications. Optical coherence tomography (OCT) is introduced as an intraoperative high-resolution imaging technique that assesses surgical breast tumor margins by providing real-time microscopic images up to 2 mm beneath the tissue surface. In a study of 37 patients split between training and study groups, OCT images covering 1 cm2 regions were acquired from surgical margins of lumpectomy specimens, registered with ink, and correlated with corresponding histological sections. A 17 patient training set used to establish standard imaging protocols and OCT evaluation criteria demonstrated that areas of higher scattering tissue with a heterogeneous pattern were indicative of tumor cells and tumor tissue, in contrast to lower scattering adipocytes found in normal breast tissue. The remaining 20 patients were enrolled into the feasibility study. Of these lumpectomy specimens, 11 were identified with a positive or close surgical margin and 9 were identified with a negative margin under OCT. Based on histological findings, 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives were found, yielding a sensitivity of 100% and specificity of 82%. These results demonstrate the potential of OCT as a real-time method for intraoperative margin assessment in breast conserving surgeries. PMID:19910294

  3. Electric Field Analysis of Breast Tumor Cells

    PubMed Central

    Sree, V. Gowri; Udayakumar, K.; Sundararajan, R.

    2011-01-01

    An attractive alternative treatment for malignant tumors that are refractive to conventional therapies, such as surgery, radiation, and chemotherapy, is electrical-pulse-mediated drug delivery. Electric field distribution of tissue/tumor is important for effective treatment of tissues. This paper deals with the electric field distribution study of a tissue model using MAXWELL 3D Simulator. Our results indicate that tumor tissue had lower electric field strength compared to normal cells, which makes them susceptible to electrical-pulse-mediated drug delivery. This difference could be due to the altered properties of tumor cells compared to normal cells, and our results corroborate this. PMID:22295214

  4. Trichostatin A and 5 Aza-2' deoxycytidine decrease estrogen receptor mRNA stability in ER positive MCF7 cells through modulation of HuR.

    PubMed

    Pryzbylkowski, Peter; Obajimi, Oluwakemi; Keen, Judith Clancy

    2008-09-01

    Trichostatin A (TSA) and 5-Aza 2'deoxycytidine (AZA), two well characterized pharmacologic inhibitors of histone deacetylation and DNA methylation, affect estrogen receptor alpha (ER) levels differently in ER-positive versus ER-negative breast cancer cell lines. Whereas pharmacologic inhibition of these epigenetic mechanisms results in re-expression and increased estrogen receptor alpha (ER) levels in ER-negative cells, treatment in ER-positive MCF7 cells results in decreased ER mRNA and protein levels. This decrease is dependent upon protein interaction with the ER 3'UTR. Actinomycin D studies showed a 37.5% reduction in ER mRNA stability from 4 to 1.5 h in AZA/TSA treated MCF7 cell lines; an effect not seen in 231ER + cells transfected with the ER coding region but lacking incorporation of the 3'UTR. AZA/TSA do not appear to directly interact with the 3'UTR but rather decrease stability through altered subcellular localization of the RNA binding protein, HuR. siRNA inhibition of HuR expression reduces both the steady-state and stability of ER mRNA, suggesting that HuR plays a critical role in the control of ER mRNA stability. Our data suggest that epigenetic modulators can alter stability through modulation of HuR subcellular distribution. Taken together, these data provide a novel anti-estrogenic mechanism for AZA and TSA in ER positive human breast cancer cells. PMID:17891453

  5. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

    PubMed

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E; Couch, Fergus J; Hopper, John L; Dite, Gillian S; Apicella, Carmel; Smith, Letitia D; Hammet, Fleur; Southey, Melissa C; Van 't Veer, Laura J; de Groot, Renate; Smit, Vincent T H B M; Fasching, Peter A; Beckmann, Matthias W; Jud, Sebastian; Ekici, Arif B; Hartmann, Arndt; Hein, Alexander; Schulz-Wendtland, Ruediger; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sinn, Hans-Peter; Sohn, Christof; Tchatchou, Sandrine; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Ørsted, David D; Kaur-Knudsen, Diljit; Milne, Roger L; Pérez, Jose I Arias; Zamora, Pilar; Rodríguez, Primitiva Menéndez; Benítez, Javier; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon-Dschun; Hamann, Ute; Fischer, Hans-Peter; Brüning, Thomas; Pesch, Beate; Chang-Claude, Jenny; Wang-Gohrke, Shan; Bremer, Michael; Karstens, Johann H; Hillemanns, Peter; Dörk, Thilo; Nevanlinna, Heli A; Heikkinen, Tuomas; Heikkilä, Päivi; Blomqvist, Carl; Aittomäki, Kristiina; Aaltonen, Kirsimari; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana M; Kataja, Vesa; Auvinen, Päivi; Eskelinen, Matti; Soini, Ylermi; Chenevix-Trench, Georgia; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Holland, Helene; Lambrechts, Diether; Claes, Bart; Vandorpe, Thijs; Neven, Patrick; Wildiers, Hans; Flesch-Janys, Dieter; Hein, Rebecca; Löning, Thomas; Kosel, Matthew; Fredericksen, Zachary S; Wang, Xianshu; Giles, Graham G; Baglietto, Laura; Severi, Gianluca; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Le Marchand, Loic; Kolonel, Laurence N; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Hunter, David J; Hankinson, Susan E; Andrulis, Irene L; Mulligan, Anna Marie; O'Malley, Frances P; Devilee, Peter; Huijts, Petra E A; Tollenaar, Rob A E M; Van Asperen, Christi J; Seynaeve, Caroline S; Chanock, Stephen J; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Figueroa, Jonine; Yang, Xiaohong R; Hooning, Maartje J; Hollestelle, Antoinette; Oldenburg, Rogier A; Jager, Agnes; Kriege, Mieke; Ozturk, Bahar; van Leenders, Geert J L H; Hall, Per; Czene, Kamila; Humphreys, Keith; Liu, Jianjun; Cox, Angela; Connley, Daniel; Cramp, Helen E; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W R; Dunning, Alison M; Easton, Douglas F; Humphreys, Manjeet K; Caldas, Carlos; Blows, Fiona; Driver, Kristy; Provenzano, Elena; Lubinski, Jan; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Gronwald, Jacek; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Shen, Chen-Yang; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Hou, Ming-Feng; Huang, Chiun-Sheng; Anton-Culver, Hoda; Ziogas, Argyrios; Pharoah, Paul D P; Garcia-Closas, Montserrat

    2011-08-15

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment. PMID:21596841

  6. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

    PubMed Central

    Broeks, Annegien; Schmidt, Marjanka K.; Sherman, Mark E.; Couch, Fergus J.; Hopper, John L.; Dite, Gillian S.; Apicella, Carmel; Smith, Letitia D.; Hammet, Fleur; Southey, Melissa C.; Van ’t Veer, Laura J.; de Groot, Renate; Smit, Vincent T.H.B.M.; Fasching, Peter A.; Beckmann, Matthias W.; Jud, Sebastian; Ekici, Arif B.; Hartmann, Arndt; Hein, Alexander; Schulz-Wendtland, Ruediger; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sinn, Hans-Peter; Sohn, Christof; Tchatchou, Sandrine; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Ørsted, David D.; Kaur-Knudsen, Diljit; Milne, Roger L.; Pérez, Jose I. Arias; Zamora, Pilar; Rodríguez, Primitiva Menéndez; Benítez, Javier; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon-Dschun; Hamann, Ute; Fischer, Hans-Peter; Brüning, Thomas; Pesch, Beate; Chang-Claude, Jenny; Wang-Gohrke, Shan; Bremer, Michael; Karstens, Johann H.; Hillemanns, Peter; Dörk, Thilo; Nevanlinna, Heli A.; Heikkinen, Tuomas; Heikkilä, Päivi; Blomqvist, Carl; Aittomäki, Kristiina; Aaltonen, Kirsimari; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana M.; Kataja, Vesa; Auvinen, Päivi; Eskelinen, Matti; Soini, Ylermi; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Holland, Helene; Lambrechts, Diether; Claes, Bart; Vandorpe, Thijs; Neven, Patrick; Wildiers, Hans; Flesch-Janys, Dieter; Hein, Rebecca; Löning, Thomas; Kosel, Matthew; Fredericksen, Zachary S.; Wang, Xianshu; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Grenaker Alnæs, Grethe; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Hunter, David J.; Hankinson, Susan E.; Andrulis, Irene L.; Marie Mulligan, Anna; O'Malley, Frances P.; Devilee, Peter; Huijts, Petra E.A.; Tollenaar, Rob A.E.M.; Van Asperen, Christi J.; Seynaeve, Caroline S.; Chanock, Stephen J.; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Figueroa, Jonine; Yang, Xiaohong R.; Hooning, Maartje J.; Hollestelle, Antoinette; Oldenburg, Rogier A.; Jager, Agnes; Kriege, Mieke; Ozturk, Bahar; van Leenders, Geert J.L.H.; Hall, Per; Czene, Kamila; Humphreys, Keith; Liu, Jianjun; Cox, Angela; Connley, Daniel; Cramp, Helen E.; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W.R.; Dunning, Alison M.; Easton, Douglas F.; Humphreys, Manjeet K.; Caldas, Carlos; Blows, Fiona; Driver, Kristy; Provenzano, Elena; Lubinski, Jan; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Gronwald, Jacek; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Shen, Chen-Yang; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Hou, Ming-Feng; Huang, Chiun-Sheng; Anton-Culver, Hoda; Ziogas, Argyrios; Pharoah, Paul D.P.; Garcia-Closas, Montserrat

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER− tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10−18), rs3803662 (16q12) (P = 3.7 × 10−5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10−6 and P = 4.1 × 10−4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment. PMID:21596841

  7. CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

    PubMed Central

    Ball, Michael S.; Shipman, Emilie P.; Kim, Hyunjung; Liby, Karen T.; Pioli, Patricia A.

    2016-01-01

    Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

  8. Second harmonic generation reveals matrix alterations during breast tumor progression

    NASA Astrophysics Data System (ADS)

    Burke, Kathleen; Tang, Ping; Brown, Edward

    2013-03-01

    Alteration of the extracellular matrix in tumor stroma influences efficiency of cell locomotion away from the primary tumor into surrounding tissues and vasculature, thereby affecting metastatic potential. We study matrix changes in breast cancer through the use of second harmonic generation (SHG) of collagen in order to improve the current understanding of breast tumor stromal development. Specifically, we utilize a quantitative analysis of the ratio of forward to backward propagating SHG signal (F/B ratio) to monitor collagen throughout ductal and lobular carcinoma development. After detection of a significant decrease in the F/B ratio of invasive but not in situ ductal carcinoma compared with healthy tissue, the collagen F/B ratio is investigated to determine the evolution of fibrillar collagen changes throughout tumor progression. Results are compared with the progression of lobular carcinoma, whose F/B signature also underwent significant evolution during progression, albeit in a different manner, which offers insight into varying methods of tissue penetration and collagen manipulation between the carcinomas. This research provides insights into trends of stromal reorganization throughout breast tumor development.

  9. CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages.

    PubMed

    Ball, Michael S; Shipman, Emilie P; Kim, Hyunjung; Liby, Karen T; Pioli, Patricia A

    2016-01-01

    Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

  10. Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy.

    PubMed

    Koren, Shany; Bentires-Alj, Mohamed

    2015-11-19

    Tumor heterogeneity impinges on prognosis, response to therapy, and metastasis. As such, heterogeneity is one of the most important and clinically relevant areas of cancer research. Breast cancer displays frequent intra- and inter-tumor heterogeneity as the result of genetic and non-genetic alterations that often enhance the vigor of cancer cells. In-depth characterization and understanding of the origin of this phenotypic and molecular diversity is paramount to improving diagnosis, the definition of prognostic and predictive biomarkers, and the design of therapeutic strategies. Here, we summarize current knowledge about sources of breast cancer heterogeneity, its consequences, and possible counter-measures. We discuss especially the impact on tumor heterogeneity of the differentiation state of the cell-of-origin, cancer cell plasticity, the microenvironment, and genetic evolution. Factors that enhance cancer cell vigor are clearly detrimental for patients. PMID:26590713

  11. Mesenchymal tumors and tumor-like lesions of the breast: a contemporary approach review.

    PubMed

    Stolnicu, Simona; Moldovan, Cosmin; Podoleanu, Cristian; Georgescu, Rares

    2015-01-01

    The classification of the breast tumors has been revised and recently published in 2012 in the WHO blue book. Contrary to the epithelial tumors in the breast, mesenchymal tumors are rare and the classification for benign and malignant tumors is based on the same criteria in both categories, since no other specific diagnostic criteria, which would have an impact on prognosis, exist to date. The present review deals with minor changes mirroring the recent developments in the benign mesenchymal tumors (new additions are nodular fasciitis and atypical vascular lesions, while the haemangiopericytoma is removed) focusing especially on criteria to diagnose sarcomas, which represent a wide spectrum including very difficult lesions. The majority of sarcomas of the breast arise as a component of a malignant phyllodes tumor, while the pure forms are very rare. When a pure primary sarcoma of the breast is diagnosed, pathologists are encouraged to categorize the lesion according to the type of differentiation and to provide to the clinicians all the important prognostic parameters for the best treatment choice. PMID:25533916

  12. Ovarian tumors in postmenopausal breast cancer patients treated with tamoxifen.

    PubMed

    Cohen, I; Beyth, Y; Tepper, R; Shapira, J; Zalel, Y; Figer, A; Cordoba, M; Yigael, D; Altaras, M M

    1996-01-01

    From September 1, 1989, to November 30, 1994, 175 menopausal breast cancer patients treated with tamoxifen were followed at the authors' institutions. During this period. 16 (9.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, for various indications. Of these, 10 (62.5%) had either uni- or bilateral ovarian tumors. The analysis of surgical findings showed an incidence of 5.7% (10/175) ovarian tumors among all the patients. In 2 (20%), the ovarian masses displayed enlargement over a relatively short period while on treatment. In 5 (50%) patients, the findings were bilateral. All tumors were detectable by ultrasonography, except four serous cystadenomas found in 3 women. The mean duration of tamoxifen treatment was 36.6 +/- 24.9 (range 9-86) months. The rate of 5.7% for ovarian tumors, in this selected group of patients, is four to five times higher than that reported for similar pathologic conditions detected by general screening with ultrasonographic scans among nonselected, asymptomatic, and untreated postmenopausal women. Two possibilities should be considered in the development of ovarian tumors coinciding with tamoxifen treatment; (1) women with breast malignancy are prone to develop benign or malignant ovarian tumors in relation to genetic factors, regardless of tamoxifen treatment; and (2) tamoxifen may stimulate enlargement of such tumors and may even cause them. PMID:8557228

  13. Infrared microspectroscopic imaging of benign breast tumor tissue sections

    NASA Astrophysics Data System (ADS)

    Fabian, H.; Lasch, P.; Boese, M.; Haensch, W.

    2003-12-01

    We have applied infrared microspectroscopic imaging for the examination of benign breast tumor tissue sections. The IR spectra of the sections were obtained by classical point microscopy with a movable stage and via a microscope equipped with a focal plane array detector. The infrared microscopic data were analysed using functional group mapping techniques and cluster analysis. The output values of the two procedures were reassembled into infrared images of the tissues, and were compared with standard staining images of the corresponding tissue region. The comparative examination of identical tissue sections by the two IR approaches enabled us to assess potential problems associated with tissue microheterogeneity. It was found that in case of fibroadenoma, a benign lesion located in breast ducts, point microscopy with a spot size of ˜30 μm is a useful practical approach which minimizes the possibility of 'contamination' of the spectra because of spectral averaging of all tissue components present in the corresponding microareas. A comparison of the spectra of the benign breast tumor with those of a malignant ductal carcinoma in situ revealed that IR microspectroscopy has the potential to differentiate between these two breast tumor types.

  14. The influence of mammographic density on breast tumor characteristics.

    PubMed

    Eriksson, Louise; Czene, Kamila; Rosenberg, Lena; Humphreys, Keith; Hall, Per

    2012-07-01

    Mammographic density (MD) is a well-established risk factor for breast cancer. Whether MD influences the tumor phenotype remains to be clarified. Previous studies are highly inconsistent and most lack important covariate information. This is a case-only study within a population-based case-control study. Cases were all postmenopausal women, aged 50-74 years, with incident breast cancer, diagnosed 1993-1995, and with no history of previous cancer (n = 2,720). 1,747 women with mammograms and information on tumor characteristics were included in analyses. MD was assessed using a computer-assisted thresholding technique. We used linear, logistic, and multinomial logistic regression, adjusting for possible confounders, to study density and tumor characteristics. PD was only statistically significantly associated with tumor size in our study (regression coefficient 0.031, p = 0.017). The effect of PD on tumor size was greater when mode of detection was excluded from the model (regression coefficient 0.043, p = 0.001). No other associations between PD and the tumor characteristics studied (lymph node metastasis, ER-status, PR-status, grade, and histopathological classification) were observed. In summary, PD was positively associated with tumor size in postmenopausal women. However, the relationship was at least partially confounded by mode of detection. Although there may be a true biological relationship between MD and more highly proliferative tumors, it also seems that part of this relationship is due to masking delaying diagnosis. In conclusion, PD does not seem to be differentially associated with tumor phenotype, except for tumor size, after taking mode of detection into consideration. PMID:22710708

  15. Predicting tumor location by modeling the deformation of the breast.

    PubMed

    Pathmanathan, Pras; Gavaghan, David J; Whiteley, Jonathan P; Chapman, S Jonathan; Brady, J Michael

    2008-10-01

    Breast cancer is one of the biggest killers in the western world, and early diagnosis is essential for improved prognosis. The shape of the breast varies hugely between the scenarios of magnetic resonance (MR) imaging (patient lies prone, breast hanging down under gravity), X-ray mammography (breast strongly compressed) and ultrasound or biopsy/surgery (patient lies supine), rendering image fusion an extremely difficult task. This paper is concerned with the use of the finite-element method and nonlinear elasticity to build a 3-D, patient-specific, anatomically accurate model of the breast. The model is constructed from MR images and can be deformed to simulate breast shape and predict tumor location during mammography or biopsy/surgery. Two extensions of the standard elasticity problem need to be solved: an inverse elasticity problem (arising from the fact that only a deformed, stressed, state is known initially), and the contact problem of modeling compression. The model is used for craniocaudal mediolateral oblique mammographic image matching, and a number of numerical experiments are performed. PMID:18838373

  16. Infrared Spectra of Human Breast Tumor Tissue and Experimental Animal Tumors

    NASA Astrophysics Data System (ADS)

    Tolstorozhev, G. B.; Belkov, M. V.; Skornyakov, I. V.; Pekhnyo, V. I.; Kozachkova, A. N.; Tsarik, H. V.; Kutsenko, I. P.; Sharykina, N. I.; Butra, V. A.

    2015-01-01

    We have used Fourier transform IR spectroscopy methods to conduct comparative studies of human breast tumors and sarcoma 180 tumor grafted into mice. The IR spectral parameters used to identify tumor tissue in mice with the sarcoma 180 strain proved to be identical to the parameters for human breast tissue in cancer. In the presence of a malignant tumor in humans, the most intense C=O vibrational bands in the protein molecules are observed in the interval 1710-1680 cm-1. For a benign tumor, in the IR spectra of breast tissue the intense bands are located in the interval 1670-1650 cm-1. We spectroscopically monitored the diagnosis and the chemotherapy process using the model of sarcoma 180 in mice. As the therapeutic drugs, we used synthesized coordination compounds based on palladium complexes with diphosphonic acid derivatives. We demonstrate the promising potential of palladium complexes with zoledronic acid as an effective cytostatic. In therapy using a palladium complex with zoledronic acid, the effect of tumor growth inhibition is accompanied by a change in its spectral characteristics. The parameters of the IR spectra for tumor tissue after treatment are close to those of the IR spectra for healthy tissue.

  17. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis.

    PubMed

    Kang, Yibin

    2016-06-01

    Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis. PMID:27184014

  18. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

    PubMed Central

    2016-01-01

    Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis. PMID:27184014

  19. Investigating mechanisms of alkalinization for reducing primary breast tumor invasion.

    PubMed

    Robey, Ian F; Nesbit, Lance A

    2013-01-01

    The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (P < 0.01). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (P ≤ 0.003). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion. PMID:23936808

  20. Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report

    PubMed Central

    Meiners, Christian

    2011-01-01

    The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated. PMID:24212668

  1. Mesenchymal Stem Cells Develop Tumor Tropism but Do Not Accelerate Breast Cancer Tumorigenesis in a Somatic Mouse Breast Cancer Model

    PubMed Central

    Usha, Lydia; Rao, Geetha; Christopherson II, Kent; Xu, Xiulong

    2013-01-01

    The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves. PMID:24069135

  2. Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival.

    PubMed

    den Hollander, Petra; Rawls, Kathryn; Tsimelzon, Anna; Shepherd, Jonathan; Mazumdar, Abhijit; Hill, Jamal; Fuqua, Suzanne A W; Chang, Jenny C; Osborne, C Kent; Hilsenbeck, Susan G; Mills, Gordon B; Brown, Powel H

    2016-04-01

    Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR = 0.05) in TNBC compared with ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific siRNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1-S cell-cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients. Cancer Res; 76(7); 1942-53. ©2016 AACR. PMID:26921331

  3. Autoantibodies to tumor-associated antigens in breast carcinoma.

    PubMed

    Piura, Ettie; Piura, Benjamin

    2010-01-01

    Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the circulation of patients with cancer. This paper will focus on recent knowledge related to circulating AAbs to TAAs in breast carcinoma. So far, the following TAAs have been identified to elicit circulating AAbs in breast carcinoma: p53, MUC-1, heat shock proteins (HSP-27, HSP-60, and HSP-90), HER2/neu/c-erb B2, GIPC-1, c-myc, c-myb, cancer-testis antigens (NY-ESO-1), BRCA1, BRCA2, endostatin, lipophilin B, cyclin B1, cyclin D1, fibulin, insulin-like growth factor binding protein 2 (IGFBP-2), topoisomerase II alpha (TOPO2α), and cathepsin D. Measurement of serum AAbs to one specific TAA only is of little value for screening and early diagnosis of breast carcinoma; however, assessment of AAbs to a panel of TAAs may have promising diagnostic potential. PMID:21113302

  4. Segmentation of ultrasonic breast tumors based on homogeneous patch

    PubMed Central

    Gao, Liang; Yang, Wei; Liao, Zhiwu; Liu, Xiaoyun; Feng, Qianjin; Chen, Wufan

    2012-01-01

    Purpose: Accurately segmenting breast tumors in ultrasound (US) images is a difficult problem due to their specular nature and appearance of sonographic tumors. The current paper presents a variant of the normalized cut (NCut) algorithm based on homogeneous patches (HP-NCut) for the segmentation of ultrasonic breast tumors. Methods: A novel boundary-detection function is defined by combining texture and intensity information to find the fuzzy boundaries in US images. Subsequently, based on the precalculated boundary map, an adaptive neighborhood according to image location referred to as a homogeneous patch (HP) is proposed. HPs are guaranteed to spread within the same tissue region; thus, the statistics of primary features within the HPs is more reliable in distinguishing the different tissues and benefits subsequent segmentation. Finally, the fuzzy distribution of textons within HPs is used as final image features, and the segmentation is obtained using the NCut framework. Results: The HP-NCut algorithm was evaluated on a large dataset of 100 breast US images (50 benign and 50 malignant). The mean Hausdorff distance measure, the mean minimum Euclidean distance measure and similarity measure achieved 7.1 pixels, 1.58 pixels, and 86.67%, respectively, for benign tumors while those achieved 10.57 pixels, 1.98 pixels, and 84.41%, respectively, for malignant tumors. Conclusions: The HP-NCut algorithm provided the improvement in accuracy and robustness compared with state-of-the-art methods. A conclusion that the HP-NCut algorithm is suitable for ultrasonic tumor segmentation problems can be drawn. PMID:22755713

  5. Accuracy of lesion boundary tracking in navigated breast tumor excision

    NASA Astrophysics Data System (ADS)

    Heffernan, Emily; Ungi, Tamas; Vaughan, Thomas; Pezeshki, Padina; Lasso, Andras; Gauvin, Gabrielle; Rudan, John; Engel, C. Jay; Morin, Evelyn; Fichtinger, Gabor

    2016-03-01

    PURPOSE: An electromagnetic navigation system for tumor excision in breast conserving surgery has recently been developed. Preoperatively, a hooked needle is positioned in the tumor and the tumor boundaries are defined in the needle coordinate system. The needle is tracked electromagnetically throughout the procedure to localize the tumor. However, the needle may move and the tissue may deform, leading to errors in maintaining a correct excision boundary. It is imperative to quantify these errors so the surgeon can choose an appropriate resection margin. METHODS: A commercial breast biopsy phantom with several inclusions was used. Location and shape of a lesion before and after mechanical deformation were determined using 3D ultrasound volumes. Tumor location and shape were estimated from initial contours and tracking data. The difference in estimated and actual location and shape of the lesion after deformation was quantified using the Hausdorff distance. Data collection and analysis were done using our 3D Slicer software application and PLUS toolkit. RESULTS: The deformation of the breast resulted in 3.72 mm (STD 0.67 mm) average boundary displacement for an isoelastic lesion and 3.88 mm (STD 0.43 mm) for a hyperelastic lesion. The difference between the actual and estimated tracked tumor boundary was 0.88 mm (STD 0.20 mm) for the isoelastic and 1.78 mm (STD 0.18 mm) for the hyperelastic lesion. CONCLUSION: The average lesion boundary tracking error was below 2mm, which is clinically acceptable. We suspect that stiffness of the phantom tissue affected the error measurements. Results will be validated in patient studies.

  6. [Mammaglobin in peripheral blood and tumor in breast cancer patients].

    PubMed

    Bozhenko, V K; Kharchenko, N V; Vaskevich, E F; Kudinova, E A; Oorzhak, A V; Rozhkova, N I; Trotsenko, I D

    2016-05-01

    Currently, no molecular biological markers do exist for early diagnosis of breast cancer. One of the possible candidates for the marker of early breast cancer is mammaglobin (MGB1) or SCGB2A2 (secretoglobin, family 2A, member 2), characterized by the maximal expression level in early breast cancer. Using the RT-PCR method MGB1 mRNA expression was examined in 57 tumor tissue samples and 57 samples of morphologically non-malignant tissue (MNT) of breast cancer (BC) patients. Specificity and sensitivity of the MGB1 mRNA assay in peripheral blood of BC patients was evaluated by nested PCR. 169 blood samples (from 95 BC patients, 22 from patients with benign breast tumors, 28 from patients with tumors of other localizations, and 24 samples from healthy donors) have been analyzed. MGB1 expression was significantly higher in BC tissue samples compared to MNT (p=0.0019). The maximal expression level was in the samples T1 (p=0.013), stage I BC (p=0.037), GI (p=0.0019). The MGB1 expression positively correlated with expression of estrogen (p = 0,034) and progesterone (p=0.0004) receptors. Sensitivity and specificity of the MGB1 mRNA assay in peripheral blood were 60.6% and 92.3%, respectively. Expression of MGB1 was higher in BC than MNT and it decreased during BC progression. The sensitivity and specificity of the MGB1 mRNA assay may be used as an additional diagnostic method. PMID:27563000

  7. Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes

    SciTech Connect

    Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Tolic, Nikola; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Fillmore, Thomas L.; Schepmoes, Athena A.; Levine, Douglas; Townsend, Reid; Davies, Sherri; Li, Shunqiang; Ellis, Matthew; Boja, Emily; Rivers, Robert; Rodriguez, Henry; Rodland, Karin D.; Liu, Tao; Smith, Richard D.

    2015-01-02

    Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification, and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, which is suitable for high throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with post-excision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.

  8. Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes

    SciTech Connect

    Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Tolic, Nikola; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Fillmore, Thomas L.; Schepmoes, Athena A.; Levine, Douglas; Townsend, Reid; Davies, Sherri; Li, Shunqiang; Ellis, Matthew; Boja, Emily; Rivers, Robert; Rodriguez, Henry; Rodland, Karin D.; Liu, Tao; Smith, Richard D.

    2015-01-01

    Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification, and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, and which is suitable for high throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with post-excision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.

  9. Harmonic Motion Microwave Doppler Imaging method for breast tumor detection.

    PubMed

    Top, Can Barıs; Tafreshi, Azadeh Kamali; Gençer, Nevzat G

    2014-01-01

    Harmonic Motion Microwave Doppler Imaging (HMMDI) method is recently proposed as a non-invasive hybrid breast imaging technique for tumor detection. The acquired data depend on acoustic, elastic and electromagnetic properties of the tissue. The potential of the method is analyzed with simulation studies and phantom experiments. In this paper, the results of these studies are summarized. It is shown that HMMDI method has a potential to detect malignancies inside fibro-glandular tissue. PMID:25571382

  10. Persistent complement activation on tumor cells in breast cancer.

    PubMed Central

    Niculescu, F.; Rus, H. G.; Retegan, M.; Vlaicu, R.

    1992-01-01

    The neoantigens of the C5b-9 complement complex, IgG, C3, C4, S-protein/vitronectin, fibronectin, and macrophages were localized on 17 samples of breast cancer and on 6 samples of benign breast tumors using polyclonal or monoclonal antibodies and the streptavidin-biotin-peroxidase technique. All the tissue samples with carcinoma in each the TNM stages presented C5b-9 deposits on the membranes of tumor cells, thin granules on cell remnants, and diffuse deposits in the necrotic areas. When chemotherapy and radiation therapy preceded surgery, C5b-9 deposits were more intense and extended. The C5b-9 deposits were absent in all the samples with benign lesions. S-protein/vitronectin was present as fibrillar deposits in the connective tissue matrix and as diffuse deposits around the tumor cells, less intense and extended than fibronectin. IgG, C3, and C4 deposits were present only in carcinoma samples. The presence of C5b-9 deposits is indicative of complement activation and its subsequent pathogenetic effects in breast cancer. Images Figure 1 PMID:1374587

  11. Dietary selenium supplementation modifies breast tumor growth and metastasis.

    PubMed

    Chen, Yu-Chi; Prabhu, K Sandeep; Das, Arunangshu; Mastro, Andrea M

    2013-11-01

    The survival rate for breast cancer drops dramatically once the disease progresses to the metastatic stage. Selenium (Se) is an essential micronutrient credited with having high anticancer and chemopreventive properties. In our study, we investigated if dietary Se supplementation modified breast cancer development in vivo. Three diets supplemented with sodium selenite, methylseleninic acid (MSA) or selenomethionine (SeMet), as well as a Se-deficient and a Se-adequate diet were fed to mice before mammary gland inoculation of 4T1.2 cells. The primary tumor growth, the numbers of cancer cells present in lungs, hearts, livers, kidneys and femurs and several proinflammatory cytokines were measured. We found that inorganic selenite supplementation provided only short-term delay of tumor growth, whereas the two organic SeMet and MSA supplements provided more potent growth inhibition. These diets also affected cancer metastasis differently. Mice fed selenite developed the most extensive metastasis and had an increased incidence of kidney and bone metastasis. On the other hand, mice fed the SeMet diet showed the least amount of cancer growth at metastatic sites. The MSA diet also provided some protection against breast cancer metastasis although the effects were less significant than those of SeMet. The cytokine profiles indicated that serum levels of interlukin-2, interleukin-6, interferon γ and vascular endothelial growth factor were elevated in SeMet-supplemented mice. There was no significant difference in tumor growth and the patterns of metastasis between the Se-deficient and Se-adequate groups. Our data suggest that organic Se supplementation may reduce/delay breast cancer metastasis, while selenite may exacerbate it. PMID:23613334

  12. Prognostic significance of Ki-67 index value at the primary breast tumor in recurrent breast cancer

    PubMed Central

    NISHIMURA, REIKI; OSAKO, TOMOFUMI; NISHIYAMA, YASUYUKI; TASHIMA, RUMIKO; NAKANO, MASAHIRO; FUJISUE, MAMIKO; TOYOZUMI, YASUO; ARIMA, NOBUYUKI

    2014-01-01

    The Ki-67 index value is a prognostic factor in primary breast cancer and is a proliferation marker that also distinguishes between luminal type A and type B breast cancer. Moreover, a change in Ki-67 index values due to treatment and recurrence is considered to be important in treating breast cancer. In this study, we investigated whether the baseline Ki-67 value in the primary tumor is useful as a prognostic factor following disease recurrence. Immunohistochemical analysis of the Ki-67 index was performed on 4,701 patients with primary breast cancer from 1987 until March, 2013. Among these patients, there were 666 consecutive cases exhibiting recurrence after primary surgery. The fraction of proliferating cells was based on a count of at least 500 tumor cells in the area including the hot spot. The Ki-67 values were divided into 3 groups, namely <20, ≥20 and ≥50%. The investigated items included estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), tumor size, nodal status for the primary tumor, recurrence site (soft tissue, bone and viscera) and disease-free interval (DFI). The Cox’s proportional hazard model was used to perform univariate and multivariate analyses of the factors associated with overall survival (OS) following recurrence. The median follow-up period was 65.9 months in the surviving group. The median Ki-67 value at baseline was 20% in all the cases and 27% in the recurrent cases. The Ki-67 values were low (24%) in patients with bone metastasis and significantly higher in patients with liver or brain metastasis (38 and 55%, respectively). Moreover, DFI was found to be inversely correlated with the Ki-67 values. Univariate analysis was performed to identify the prognostic factors for OS after recurrence. The significant factors included tumor size, lymph node status, ER, PgR, DFI, recurrence site and Ki-67 index value. Among these factors, a multivariate analysis identified the Ki-67 index value

  13. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

    PubMed

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van't; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-Gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter

    2013-04-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733

  14. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    PubMed Central

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van’t; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Silva, Isabel dos Santos; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; Van den Ouweland, Ans M W; Van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733

  15. Tailoring Chemotherapy in Early-Stage Breast Cancer: Based on Tumor Biology or Tumor Burden?

    PubMed

    Ribnikar, Domen; Cardoso, Fatima

    2016-01-01

    The question of whether to offer adjuvant chemotherapy to patients with early-stage breast cancer has always been challenging to answer. It is well known that a substantial proportion of patients with early-stage breast cancer are over treated, especially when staging and hormonal and HER2 receptors are solely taken into consideration. The advances in our knowledge of breast cancer biology and its clinical implications were the basis for the discovery of additional reliable prognostic markers to aid decision making for adjuvant treatment. Gene expression profiling is a molecular tool that more precisely defines the intrinsic characteristics of each individual tumor. The application of this technology has led to the development of gene signatures/profiles with relevant prognostic-and some predictive-value that have become important tools in defining which patients with early-stage breast cancer can be safely spared from chemotherapy. However, the exact clinical utility of these tools will only be determined after the results of two large prospective randomized trials, MINDACT and TailorX, evaluating their role become available. Notwithstanding the existence of these genomic tools, tumor burden (defined as tumor size and nodal status) still has independent prognostic value and must be incorporated in decision making. In addition, these gene signatures have limited predictive value, and new biomarkers and new targets are needed. Therefore close collaboration between clinicians and scientists is crucial. Lastly, issues of cost-effectiveness, reimbursement, and availability are crucial and widely variable around the globe. PMID:27249737

  16. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information.

    PubMed

    Feeley, Linda P; Mulligan, Anna M; Pinnaduwage, Dushanthi; Bull, Shelley B; Andrulis, Irene L

    2014-04-01

    The objectives of this study were to determine the prognostic significance of subgrouping estrogen receptor (ER)-positive breast tumors into low- and high-risk luminal categories using Ki67 index, TP53, or progesterone receptor (PR) status. The study group comprised 540 patients with lymph node negative, invasive breast carcinoma. Luminal A subtype was defined as being ER positive, HER2 negative, and Ki67 low (<14% cells positive) and luminal B subtype as being ER positive, HER2 negative, and Ki67 high (≥ 14% cells positive). Luminal tumors were also subgrouped into risk categories based on the PR and TP53 status. Survival analysis was performed. Patients with luminal B tumors (n=173) had significantly worse disease-free survival compared to those with luminal A tumors (n=186) (log rank P-value=0.0164; univariate Cox regression relative risk 2.00; 95% CI, 1.12-3.58; P=0.0187). Luminal subtype remained an independent prognostic indicator on multivariate analysis including traditional prognostic factors (relative risk 2.12; 95% CI, 1.16-3.88; P=0.0151). Using TP53 status or PR negativity rather than Ki67 to classify ER-positive luminal tumors gave similar outcome results to those obtained using the proliferation index. However, it was a combination of the three markers, which proved the most powerful prognostically. Ki67 index, TP53 status, or PR negativity can be used to segregate ER-positive, HER2-negative tumors into prognostically meaningful subgroups with significantly different clinical outcomes. These biomarkers particularly in combination may potentially be used clinically to guide patient management. PMID:24051696

  17. Effects of Tumor Microenvironment Heterogeneity on Nanoparticle Disposition and Efficacy in Breast Cancer Tumor Models

    PubMed Central

    Song, Gina; Darr, David B.; Santos, Charlene M.; Ross, Mark; Valdivia, Alain; Jordan, Jamie L.; Midkiff, Bentley R.; Cohen, Stephanie; Feinberg, Nana Nikolaishvili; Miller, C. Ryan; Tarrant, Teresa K.; Rogers, Arlin B.; Dudley, Andrew C.; Perou, Charles M.; Zamboni, William C.

    2014-01-01

    Purpose Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy. Experimental designs C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53Null orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg intravenously (IV) x1. Area-under-the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by immunohistochemistry. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg IV weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed. Results Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin were similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P<0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and vascular endothelial growth factor (VEGF)-a, greater vascular quantity, and decreased expression of VEGF-c compared to C3-TAg (P<0.05). PLD was more efficacious compared to NL-doxo in both models. Conclusion The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes. PMID:25231403

  18. Ewing’s Sarcoma: An Uncommon Breast Tumor

    PubMed Central

    Meddeb, Sawsen; Rhim, Mohamed Salah; Kouira, Mouna; Mestiri, Sarra; Bibi, Mohamed; Yacoubi, Mohamed Tahar

    2014-01-01

    Ewing’s sarcoma/primitive neuroectodermal tumors (EWS/PNET) are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno-phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22) translocation. PMID:25332765

  19. Adipose-Derived Stromal Vascular Fraction Differentially Expands Breast Progenitors in Tissue Adjacent to Tumors Compared to Healthy Breast Tissue

    PubMed Central

    Chatterjee, Sumanta; Laliberte, Mike; Blelloch, Sarah; Ratanshi, Imran; Safneck, Janice; Buchel, Ed

    2015-01-01

    Background: Autologous fat grafts supplemented with adipose-derived stromal vascular fraction are used in reconstructive and cosmetic breast procedures. Stromal vascular fraction contains adipose-derived stem cells that are thought to encourage wound healing, tissue regeneration, and graft retention. Although use of stromal vascular fraction has provided exciting perspectives for aesthetic procedures, no studies have yet been conducted to determine whether its cells contribute to breast tissue regeneration. The authors examined the effect of these cells on the expansion of human breast epithelial progenitors. Methods: From patients undergoing reconstructive breast surgery following mastectomies, abdominal fat, matching tissue adjacent to breast tumors, and the contralateral non–tumor-containing breast tissue were obtained. Ex vivo co-cultures using breast epithelial cells and the stromal vascular fraction cells were used to study the expansion potential of breast progenitors. Breast reduction samples were collected as a source of healthy breast cells. Results: The authors observed that progenitors present in healthy breast tissue or contralateral non–tumor-containing breast tissue showed significant and robust expansion in the presence of stromal vascular fraction (5.2- and 4.8-fold, respectively). Whereas the healthy progenitors expanded up to 3-fold without the stromal vascular fraction cells, the expansion of tissue adjacent to breast tumor progenitors required the presence of stromal vascular fraction cells, leading to a 7-fold expansion, which was significantly higher than the expansion of healthy progenitors with stromal vascular fraction. Conclusions: The use of stromal vascular fraction might be more beneficial to reconstructive operations following mastectomies compared with cosmetic corrections of the healthy breast. Future studies are required to examine the potential risk factors associated with its use. CLINICAL QUESTION/LEVEL OF EVIDENCE

  20. Radiation-Associated Breast Tumors Display a Distinct Gene Expression Profile

    SciTech Connect

    Broeks, Annegien; Braaf, Linde M.; Wessels, Lodewyk F.A.; Vijver, Marc van de; De Bruin, Marie L.; Stovall, Marilyn; Russell, Nicola S.; Leeuwen, Flora E. van; Van't Veer, Laura J.

    2010-02-01

    Purpose: Women who received irradiation for Hodgkin's lymphoma have a strong increased risk for developing breast cancer. Approximately 90% of the breast cancers in these patients can be attributed to their radiation treatment, rendering such series extremely useful to determine whether a common radiation-associated cause underlies the carcinogenic process. Methods and Materials: In this study we used gene expression profiling technology to assess gene expression changes in radiation-associated breast tumors compared with a set of control breast tumors of women unexposed to radiation, diagnosed at the same age. RNA was obtained from fresh frozen tissue samples from 22 patients who developed breast cancer after Hodgkin's lymphoma (BfHL) and from 20 control breast tumors. Results: Unsupervised hierarchical clustering of the profile data resulted in a clustering of the radiation-associated tumors separate from the control tumors (p < 0.001). Using a supervised class prediction tool, a nearest centroid classifier of 198 probes was identified. The BfHL tumors were often of the intrinsic basal breast tumor subtype, and they showed a chromosomal instability profile and a higher expression of the proliferation marker Ki-67. Conclusion: These results indicate that radiation-associated tumors are different from other breast tumors on the basis of their expression profile and that they are mainly of one specific cause that is characterized by high proliferation and a more aggressive tumor type.

  1. Heterogeneity of Bcl-2 expression in metastatic breast carcinoma.

    PubMed

    Subhawong, Andrea Proctor; Nassar, Hind; Halushka, Marc K; Illei, Peter B; Vang, Russell; Argani, Pedram

    2010-08-01

    Bcl-2 is an antiapoptotic protein that promotes cell survival, but also may block proliferation. In breast cancer, bcl-2 expression correlates with favorable prognosis and estrogen receptor (ER) positivity. However, experimental data have paradoxically suggested that bcl-2 promotes chemoresistance and metastasis. A direct and comprehensive comparison of bcl-2 expression between primary breast carcinomas and paired distant metastases has not been performed. We completed rapid autopsies on 17 patients with archived primary tumors and metastatic breast carcinoma, and created single-patient tissue microarrays containing each patient's primary tumor and matched metastases. Expression of bcl-2, ER, progesterone receptor, and HER-2 in primary tumors and matched metastases were compared by immunohistochemistry. All 11 ER-positive cases showed bcl-2 labeling in the primary tumor, whereas only 3 of 6 ER-negative cases did (P=0.029). In 10 cases, bcl-2 labeling in metastases was similar to that of the primary, although 3 cases showed significant variation among metastases. In six other cases, bcl-2 labeling was lost or significantly diminished in metastases. Five of the latter cases were Luminal A (ER-positive, HER-2-negative) primaries, three of which lost hormone receptors in metastases. Only 1 of 17 cases showed an increase in bcl-2 labeling in metastases compared with the paired primary tumor. In conclusion, bcl-2 is infrequently upregulated in metastatic breast carcinoma. Instead, downregulation of bcl-2 expression may occur in the setting of hormone therapy resistance. Our findings call into question the potential utility of anti-bcl-2 therapy in metastatic breast cancer. PMID:20495533

  2. Mucins and Cytokeratins as Serum Tumor Markers in Breast Cancer.

    PubMed

    Nicolini, Andrea; Ferrari, Paola; Rossi, Giuseppe

    2015-01-01

    Structural and functional characteristics of mucins and cytokeratins are shortly described. Thereafter, those commonly used in breast cancer as serum tumor markers are considered. First CA15.3, MCA, CA549, CA27.29 mucins and CYFRA21.1, TPA, TPS cytokeratins alone or in association have been examined in different stages and conditions. Then their usefulness in monitoring disease-free breast cancer patients is evaluated. The central role of the established cut-off and critical change, the "early" treatment of recurrent disease and the potential benefit in survival are other issues that have been highlighted and discussed. The successive sections and subsections deal with the monitoring of advanced disease. In them, the current recommendations and the principal findings on using the above mentioned mucins and cytokeratins have been reported. A computer program for interpreting consecutive measurements of serum tumor markers also has been illustrated. The final part of the chapter is devoted to mucins and cytokeratins as markers of circulating and disseminated tumor cells and their usefulness for prognosis. PMID:26530368

  3. Does Mammographic Density Distribution Correlate with Location of Breast Cancer Tumors?

    NASA Astrophysics Data System (ADS)

    Yu, Clare; Mitchell, James

    2013-03-01

    The risk of breast cancer is higher in women with denser, stiffer breasts. In mammograms, one measure of breast density is mammographic density. Mammograms involve x-rays, and radiodense material is characterized by white areas on a mammogram. The more white areas there are, the higher the mammographic density and the higher the risk of breast cancer. It is also known that most breast tumors occur in the upper half of the breast. Actually, about half of breast tumors occur in the upper outer quadrant of the breast near the armpit. We have analyzed mammograms and find that the mammographic density (white stuff) is higher in the upper half of the breast where there is more tissue. This work is supported by the National Cancer Institute through the Princeton Physical Sciences Oncology Center.

  4. GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer.

    PubMed

    Yang, Zheqiong; Peng, Min; Cheng, Liang; Jones, Kimya; Maihle, Nita J; Mivechi, Nahid F; Ko, Lan

    2016-05-01

    Human breast cancer precursor cells remain to be elucidated. Using breast cancer gene product GT198 (PSMC3IP; alias TBPIP or Hop2) as a unique marker, we revealed the cellular identities of GT198 mutant cells in human breast tumor stroma. GT198 is a steroid hormone receptor coactivator and a crucial factor in DNA repair. Germline mutations in GT198 are present in breast and ovarian cancer families. Somatic mutations in GT198 are present in ovarian tumor stromal cells. Herein, we show that human breast tumor stromal cells carry GT198 somatic mutations and express cytoplasmic GT198 protein. GT198(+) stromal cells share vascular smooth muscle cell origin, including myoepithelial cells, adipocytes, capillary pericytes, and stromal fibroblasts. Frequent GT198 mutations are associated with GT198(+) tumor stroma but not with GT198(-) tumor cells. GT198(+) progenitor cells are mostly capillary pericytes. When tested in cultured cells, mutant GT198 induces vascular endothelial growth factor promoter, and potentially promotes angiogenesis and adipogenesis. Our results suggest that multiple lineages of breast tumor stromal cells are mutated in GT198. These findings imply the presence of mutant progenitors, whereas their descendants, carrying the same GT198 mutations, are collectively responsible for forming breast tumor microenvironment. GT198 expression is, therefore, a specific marker of mutant breast tumor stroma and has the potential to facilitate diagnosis and targeted treatment of human breast cancer. PMID:27001628

  5. A case of tumor-forming pseudoangiomatous stromal hyperplasia of the breast.

    PubMed

    Takagi, Hiroyuki; Miyairi, Junichi; Hata, Motoyuki; Kirii, Yasusi; Tsuchiya, Shinichi

    2013-04-01

    Pseudoangiomatous stromal hyperplasia (PASH), characterized by the presence of slit-like spaces embedded in a hyalinized stroma, is sometimes observed during pathologic examination of breast-tissue specimens. Because tumor-forming PASH is rare, we report a case of a 41-year-old woman admitted to our hospital with a tumor in her left breast. Ultrasonography and aspiration biopsy cytology revealed a benign tumor. After performing Mammotome(®) biopsy, the lesion was diagnosed as PASH of the breast based on characteristic findings of histology and immunohistochemical studies. Because PASH tumors do not usually become malignant, we decided to perform ultrasonographic follow-up without tumor excision. PMID:20072822

  6. Computer-Aided Assessment of Tumor Grade for Breast Cancer in Ultrasound Images

    PubMed Central

    2015-01-01

    This study involved developing a computer-aided diagnosis (CAD) system for discriminating the grades of breast cancer tumors in ultrasound (US) images. Histological tumor grades of breast cancer lesions are standard prognostic indicators. Tumor grade information enables physicians to determine appropriate treatments for their patients. US imaging is a noninvasive approach to breast cancer examination. In this study, 148 3-dimensional US images of malignant breast tumors were obtained. Textural, morphological, ellipsoid fitting, and posterior acoustic features were quantified to characterize the tumor masses. A support vector machine was developed to classify breast tumor grades as either low or high. The proposed CAD system achieved an accuracy of 85.14% (126/148), a sensitivity of 79.31% (23/29), a specificity of 86.55% (103/119), and an AZ of 0.7940. PMID:25810750

  7. [Benign phylloides tumor of the breast. Considerations on a clinical case].

    PubMed

    Biondi, Antonio; Di Giuntao, Michela; Motta, Salvatore; Privitera, Giuseppe; Fichera, Debora Simona; Ciuni, Roberto; Basile, Francesco

    2009-01-01

    Phyllodes tumors are unusual biphasic fibroepithelial neoplasms of the breast, accounting for < 1% of all breast tumors and raising issues of diagnosis and therapeutic choice. They can grow quickly and when the maximum diameter is greater than 10 cm. We talk about giant phyllodes tumors. Ultrasound, Mammography and FNA are not effective. A potentially useful diagnostic modality is MRI. Core tissue biopsy or incisional biopsy represent the preferred means of pre-operative diagnosis. Conservative treatment can be effective also in giant tumors depending upon the size of the tumor and the breast if a complete excision with an adequate margin of normal breast tissue can be achieved, so avoiding local recurrence often accompanied by worse histopathology. The Authors report the case of a giant benign phyllode tumor of the breast treated with conservative surgery, quadrantectomy and oncoplasty. No local recurrence at 4 years follow-up. PMID:20476682

  8. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    SciTech Connect

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  9. Non-steroidal anti-inflammatory drug use, hormone receptor status, and breast cancer-specific mortality in the Carolina Breast Cancer Study.

    PubMed

    Allott, E H; Tse, C-K; Olshan, A F; Carey, L A; Moorman, P G; Troester, M A

    2014-09-01

    Epidemiologic studies report a protective association between non-steroidal anti-inflammatory drug (NSAID) use and hormone receptor-positive breast cancer risk, a finding consistent with NSAID-mediated suppression of aromatase-driven estrogen biosynthesis. However, the association between NSAID use and breast cancer-specific mortality is uncertain and it is unknown whether this relationship differs by hormone receptor status. This study comprised 935 invasive breast cancer cases, of which 490 were estrogen receptor (ER)-positive, enrolled between 1996 and 2001 in the Carolina Breast Cancer Study. Self-reported NSAID use in the decade prior to diagnosis was categorized by duration and regularity of use. Differences in tumor size, stage, node, and receptor status by NSAID use were examined using Chi-square tests. Associations between NSAID use and breast cancer-specific mortality were examined using age- and race-adjusted Cox proportional hazards analysis. Tumor characteristics did not differ by NSAID use. Increased duration and regularity of NSAID use was associated with reduced breast cancer-specific mortality in women with ER-positive tumors (long-term regular use (≥8 days/month for ≥ 3 years) versus no use; hazard ratio (HR) 0.48; 95 % confidence interval (CI) 0.23-0.98), with a statistically significant trend with increasing duration and regularity (p-trend = 0.036). There was no association for ER-negative cases (HR 1.19; 95 %CI 0.50-2.81; p-trend = 0.891). Long-term, regular NSAID use in the decade prior to breast cancer diagnosis was associated with reduced breast cancer-specific mortality in ER-positive cases. If confirmed, these findings support the hypothesis that potential chemopreventive properties of NSAIDs are mediated, at least in part, through suppression of estrogen biosynthesis. PMID:25151293

  10. Simulation of holographic radar application in detection of breast tumors

    NASA Astrophysics Data System (ADS)

    Alborova, I. L.; Anishchenko, Lesya

    2014-05-01

    This paper presents the results of experiments and mathematical simulation carried out to confirm the possibility of using holographic radar for the detection of breast tumors. In the work the software designed for the numerical solution of electromagnetic problems using the Finite-Difference Time-Domain Method. The simulation was performed with the three probe frequencies 4, 7 and 15 GHz. The model is a parallelepiped with dimensions 200×200×100 mm - mimicking the normal tissue of the breast, with the inclusion of a sphere - malignant neoplasm of breast tissue, the radius and depth of which have been varied. Frequency dispersion of normal and malignant tissues dielectric properties (conductivity and permittivity) was taken into account. It was shown both by theoretical and experimental results that it is preferable to use lower-frequency probing signal, namely, 4GHz, which can detect the inclusion of 5 mm diameter up to a depth of 10 mm. While using of probing signals of 7 and 15 GHz the depth limit of detection inclusion is not more than 5 mm, which is caused by the high attenuation in a medium. However, their usage is preferred because of higher resolution.

  11. Characterization of Breast Tumors Using Diffusion Kurtosis Imaging (DKI)

    PubMed Central

    Zhang, Junxiang; Chang, Shixing; Hu, Jiani; Dai, Yongming

    2014-01-01

    Aim The aim of this study was to investigate and evaluate the role of magnetic resonance (MR) diffusion kurtosis imaging (DKI) in characterizing breast lesions. Materials and Methods One hundred and twenty-four lesions in 103 patients (mean age: 57±14 years) were evaluated by MR DKI performed with 7 b-values of 0, 250, 500, 750, 1,000, 1,500, 2,000 s/mm2 and dynamic contrast-enhanced (DCE) MR imaging. Breast lesions were histologically characterized and DKI related parameters—mean diffusivity (MD) and mean kurtosis (MK)—were measured. The MD and MK in normal fibroglandular breast tissue, benign and malignant lesions were compared by One-way analysis of variance (ANOVA) with Tukey's multiple comparison test. Receiver operating characteristic (ROC) analysis was performed to assess the sensitivity and specificity of MD and MK in the diagnosis of breast lesions. Results The benign lesions (n = 42) and malignant lesions (n = 82) had mean diameters of 11.4±3.4 mm and 35.8±20.1 mm, respectively. The MK for malignant lesions (0.88±0.17) was significantly higher than that for benign lesions (0.47±0.14) (P<0.001), and, in contrast, MD for benign lesions (1.97±0.35 (10−3 mm2/s)) was higher than that for malignant lesions (1.20±0.31 (10−3 mm2/s)) (P<0.001). At a cutoff MD/MK 1.58 (10−3 mm2/s)/0.69, sensitivity and specificity of MD/MK for the diagnosis of malignant were 79.3%/84.2% and 92.9%/92.9%, respectively. The area under the curve (AUC) is 0.86/0.92 for MD/MK. Conclusions DKI could provide valuable information on the diffusion properties related to tumor microenvironment and increase diagnostic confidence of breast tumors. PMID:25406010

  12. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma

    PubMed Central

    Panis, C.; Victorino, V. J.; Herrera, A. C. S. A.; Cecchini, A. L.; Simão, A. N. C.; Tomita, L. Y.; Cecchini, R.

    2016-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide. PMID:26697139

  13. Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

    NASA Astrophysics Data System (ADS)

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-03-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

  14. Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

    PubMed Central

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-01-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis. PMID:24651154

  15. Inorganic nanovehicle targets tumor in an orthotopic breast cancer model.

    PubMed

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-01-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis. PMID:24651154

  16. Expression of DNA damage response genes indicate progressive breast tumors.

    PubMed

    Gochhait, Sailesh; Dar, Surabhi; Pal, Ranjana; Gupta, Pawan; Bamezai, Rameshwar N K

    2009-01-18

    To assess how the abnormal expression of DNA damage response (DDR) genes correlate with oncogenesis, we analyzed mRNA levels of ATM-CHK2-P53 axis in 65 sporadic breast tumors by real-time PCR followed by evaluation of P53 protein and its activation status in representative samples. Univariate analysis showed a significantly higher transcript level for ATM (P=0.002), MDM2 (P=0.015) and p21 (P=0.013) in stage 1 tumors when compared against those of later stages. Although p53 transcript levels showed the characteristic increase in stage 1, a fourfold increase of p53 in N3 tumors than other nodal stages (P=0.0007) significantly increased its expression in stage 3B. The accumulated p53 at stage 3B, confirmed also at the protein level (P=0.012), was rendered nonfunctional by reduced P53 activation (p-P53Ser15; P=0.00007) or increased rate of mutation, substantiated further by the corresponding failure of upregulation of downstream genes, MDM2 and p21. We conclude that the alteration of DDR expression facilitates tumor progression and its possible therapeutic implications need to be studied in future. PMID:18805634

  17. Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors

    PubMed Central

    Liang, Yayun; Besch-Williford, Cynthia; Benakanakere, Indira; Thorpe, Philip E.

    2010-01-01

    Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of

  18. Ipsilateral Breast Tumor Relapse: Local Recurrence Versus New Primary Tumor and the Effect of Whole-Breast Radiotherapy on the Rate of New Primaries

    SciTech Connect

    Gujral, Dorothy M.; Sumo, Georges; Owen, John R.; Ashton, Anita; Bliss, Judith M.; Haviland, Joanne; Yarnold, John R.

    2011-01-01

    Purpose: The justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT. Methods and Materials: We retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up. Results: At a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC. Conclusions: This analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy.

  19. Three-dimensional in vitro co-culture model of breast tumor using magnetic levitation.

    PubMed

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R; Dave, Bhuvanesh; Godin, Biana

    2014-01-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors. PMID:25270048

  20. Three-Dimensional In Vitro Co-Culture Model of Breast Tumor using Magnetic Levitation

    PubMed Central

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R.; Dave, Bhuvanesh; Godin, Biana

    2014-01-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors. PMID:25270048

  1. CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling.

    PubMed

    Kang, J M; Park, S; Kim, S J; Hong, H Y; Jeong, J; Kim, H-S; Kim, S-J

    2012-12-13

    Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-β (TGF-β) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, PAI-I and CDK inhibitors such as p15(INK4b) and p21(Cip1). Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity. PMID:22310290

  2. Breast Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Breast Cancer What is Breast Cancer? How Tumors Form The body is made up ... tumors form in the breast tissue. Who Gets Breast Cancer? Breast cancer is one of the most common ...

  3. Didymin reverses phthalate ester-associated breast cancer aggravation in the breast cancer tumor microenvironment

    PubMed Central

    HSU, YA-LING; HSIEH, CHIA-JUNG; TSAI, EING-MEI; HUNG, JEN-YU; CHANG, WEI-AN; HOU, MING-FENG; KUO, PO-LIN

    2016-01-01

    The present study demonstrated two novel findings. To the best of our knowledge, it is the first study to demonstrate that regulated upon activation, normal T-cell expressed and secreted (RANTES), produced by breast tumor-associated monocyte-derived dendritic cells (TADCs) following breast cancer cell exposure to phthalate esters, may contribute to the progression of cancer via enhancement of cancer cell proliferation, migration and invasion. Furthermore, the present study revealed that didymin, a dietary flavonoid glycoside present in citrus fruits, was able to reverse phthalate ester-mediated breast cancer aggravation. MDA-MB-231 cells were treated with butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP) or di-2-ethylhexyl phthalate (DEHP). Subsequently, the conditioned medium (CM) was harvested and cultured with monocyte-derived dendritic cells (mdDCs). Cultures of MDA-MB-231 cells with the conditioned medium of BBP-, DBP- or DEHP-MDA-MB-231 tumor-associated mdDCs (BBP-, DBP- or DEHP-MDA-TADC-CM) demonstrated enhanced proliferation, migration and invasion. Exposure of the MDA-MB-231 cells to DBP induced the MDA-TADCs to produce the inflammatory cytokine RANTES, which subsequently induced MDA-MB-231 cell proliferation, migration and invasion. Depleting RANTES reversed the effects of DBP-MDA-TADC-mediated MDA-MB-231 cell proliferation, migration and invasion. In addition, didymin was observed to suppress phthalate-mediated breast cancer cell proliferation, migration and invasion. The present study suggested that didymin was capable of preventing phthalate ester-associated cancer aggravation. PMID:26893687

  4. Breast cancer-specific mortality in small-sized tumor with node-positive breast cancer: a nation-wide study in Korean breast cancer society.

    PubMed

    Ryu, Jai Min; Lee, Hyouk Jin; Yoon, Tae In; Lee, Eun Sook; Lee, Soo Jung; Jung, Jin Hyang; Chae, Byung Joo; Nam, Seok Jin; Lee, Jeong Eon; Lee, Se Kyung; Bae, Soo Youn; Yu, Jonghan; Kim, Seok Won

    2016-10-01

    Tumor size and number of lymph node (LN) metastases are well known as the most important prognostic factors of breast cancer. We hypothesized that very small breast cancers with LN metastasis represent a progressive biologic behavior and evaluated tumor size stratified by LN metastasis. Data between 1990 and 2010 were obtained retrospectively from the Korean Breast Cancer Society Registry with inclusion criteria of female, non-metastatic, unilateral, and T1/2 breast cancer. We collected the following variables: age at surgery, tumor size, number of LN metastases, nuclear grade (NG), lymphovascular invasion (LVI), estrogen receptor status, progesterone receptor status, and epidermal growth factor receptor-2 status. Patient characteristics were compared by means of independent t-tests for continuous variables and the Chi-square or Fisher's exact test for categorical variables. Kaplan-Meier curves, with corresponding results of log-rank tests, were constructed for breast cancer-specific survival (BCSS). Five- and eight-year breast cancer-specific mortality (BCSM) was obtained in groups of 300 patients, followed by smoothing according to the confidence interval using the lowess method. We identified 39,826 breast cancer patients who met the inclusion criteria. Among them, 1433 (3.6 %) patients died due to breast cancer. The median follow-up duration was 63.4 (3-255) months. In the multivariate analysis, age at surgery, NG, LVI, subtype, and tumor size-nodal interactions were independently associated with BCSM. The N1 group had lower BCSS for T1a than T1b. The N2+ group also had lower BCSS for T1b than T1c or T2. In the N1 group of tumors smaller than 10 mm, 5- and 8-year BCSM decreased with larger tumor size. Patients with very small tumors with LN metastasis have decreased BCSM according to increase tumor size. Small tumors with LN metastasis could have aggressive biological behavior. PMID:27590199

  5. Truncated forms of DNA-binding estrogen receptors in human breast cancer.

    PubMed Central

    Scott, G K; Kushner, P; Vigne, J L; Benz, C C

    1991-01-01

    The likelihood a breast cancer will respond to antiestrogen therapy depends on the tumor content of immunoreactive or ligand-binding estrogen receptor (ER). To investigate the failure of many ER-positive breast cancers to respond to antiestrogen therapy, we examined by gel-shift assay the ability of tumor ER to bind its cognate estrogen response element (ERE). Analysis of 38 primary breast cancers showed that some tumors containing abundant immunoreactive ER failed to demonstrate DNA binding ER. In many other ER-positive tumors, the fraction of DNA binding ER was low and consisted primarily of truncated receptor forms, which on Western analysis were revealed to be 50 kD homodimers and 67-50 kD ER heterodimers. The use of protease inhibitors during tumor extraction and the demonstration of nuclear-localizing ER and ERE-binding COUP (chicken ovalbumin upstream promoter) protein in these tumors indicated that the truncated forms of ER were likely present in vivo. The presence of intact DNA binding ER correlated with higher tumor content of immunoreactive sex steroid receptors (ER and/or PR), standard predictors of tumor responsiveness to antiestrogen, suggesting that loss or truncation of DNA binding ER may be an important prognostic parameter accounting for some forms of clinical resistance to antiestrogen therapy. Images PMID:1864980

  6. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    PubMed Central

    Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-01-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  7. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer.

    PubMed

    Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-04-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  8. Expression of Androgen Receptor in Estrogen Receptor–positive Breast Cancer

    PubMed Central

    Ziolkowski, Piotr; Grzebieniak, Zygmunt; Jelen, Michal; Bobinski, Piotr; Agrawal, Siddarth

    2016-01-01

    Objectives: The aim of the study was to estimate the implications of androgen receptor (AR) expression in estrogen receptor (ER)-positive subset of invasive breast carcinoma patients. Patients and Methods: We assessed the AR expression in a subset of 96 predominantly ER-positive invasive breast carcinomas and correlated this expression pattern with several clinical and pathologic parameters: histologic type and grade, tumor size, lymph node status, progesterone receptor (PgR) status, and human epidermal growth factor receptor type 2 (HER2) overexpression and evaluated the association of these parameters with 10-year survival using univariate and multivariate analyses. Data used for analysis were derived from medical records. Immunohistochemical analysis for AR, ER, PgR, and HER2 were carried out and semiquantitative evaluation of stainings was performed. Results: AR expression was demonstrated in 43.7% of patients. AR was significantly related to well-differentiated tumors and positive PgR/HER2 status. No statistical difference was demonstrated in AR expression in relation to tumor size, lymph node status, menopausal status, and tumor histologic type. AR expression was not an independent prognostic factor related to 10-year survival in ER-positive cancers. In multivariate analyses, older age at diagnosis, larger tumor size, and positive lymph node status were significantly associated with poorer 10-year survival. Conclusions: AR expression is significantly associated with ER/PgR/HER2 status and positively related to well-differentiated tumors. Although AR status in ER-positive cancers is not an independent prognostic factor, it might provide important additional information on prognosis and become a promising object for targeted therapy. PMID:26230371

  9. Combined thermal and elastic modeling of the normal and tumorous breast

    NASA Astrophysics Data System (ADS)

    Jiang, Li; Zhan, Wang; Loew, Murray

    2008-03-01

    The abnormal thermogram has been shown to be a reliable indicator of a high risk of breast cancer, but an open question is how to quantify the complex relationships between the breast thermal behaviors and the underlying physiological/pathological conditions. Previous thermal modeling techniques generally did not utilize the breast geometry determined by the gravity-induced elastic deformations arising from various body postures. In this paper, a 3-D finite-element method is developed for combined modeling of the thermal and elastic properties of the breast, including the mechanical nonlinearity associated with large deformations. The effects of the thermal and elastic properties of the breast tissues are investigated quantitatively. For the normal breast in a standing/sitting up posture, the gravity-induced deformation alone is found to be able to cause an asymmetric temperature distribution even though all the thermal/elastic properties are symmetrical, and this temperature asymmetry increases for softer and more compressible breast tissues. For a tumorous breast, we found that the surface-temperature alterations generally can be recognizable for superficial tumors at depths less than 20 mm. Tumor size plays a less important role than the tumor depth in determining the tumor-induced temperature difference. This result may imply that a higher thermal sensitivity is critical for a breast thermogram system when deeper tumors are present, even if the tumor is relatively large. We expect this new method to provide a stronger foundation for, and greater specificity and precision in, thermographic diagnosis and treatment of breast tumors.

  10. Multimodality assessment of breast tumor physiology and metabolism

    NASA Astrophysics Data System (ADS)

    Chaudhry, Muhammad; Rosen, Mark; Schultz, Susan; Englander, Sarah; Sehgal, S.; Tomaszewski, M.; Schnall, Mitchell

    2005-04-01

    The objective is to compare power Doppler sonography (PD) and dynamic contrast-enhanced MRI (MR) and PET SUV in assessing the vascularity of benign and malignant breast lesions. Sixty two patients with 89 lesions (59 malignant lesions, 30 benign lesions) were evaluated by PD, MRI (MR) and PET SUV prior to surgery. Each imaging modality was evaluated independently. Lesion vascularity on PD was graded as avascular, intermediately vascular, or hypervascular. On MR, degree of maximal enhancement (minimal, moderate, or marked) and the kinetic pattern of enhancement (persistent, plateau, washout) were graded separately. For malignant lesions, PET SUV values were correlated with MRI kinetics. Gamma variable analysis was performed to assess the degree of correlation. Of the 89 lesions 44 were invasive ductal carcinoma, 2 were intraductal cancers, 6 were invasive lobular carcinoma, and 7 were invasive cancers with mixture of ductal and lobular features. There was a high degree of correlation between degree of maximal enhancement and enhancement kinetics on MRI (G=0.074, p<0.0001). The correlation between CDS and degree of maximal gadolinium enhancement was moderate (G=0.57, p=0.02). The correlation between PD vascularity and gadolinium enhancement kinetics was weak (G=0.37, p=0.12). Invasive malignancy demonstrated moderate correlation between SUV and MRI kinetics (G=0.64, p=0.14). There is a variable degree of correlation between various imaging modalities in assessing breast lesion vascularity. Further evaluation on the relationship between subjective reader assessment and objective quantitative image analysis is required to elucidate the differences in these measures of breast tumor physiology. This work was supported in part by the NIH grant P01CA085424-03.

  11. Multiplexed ion beam imaging (MIBI) of human breast tumors

    PubMed Central

    Angelo, Michael; Bendall, Sean C.; Finck, Rachel; Hale, Matthew B.; Hitzman, Chuck; Borowsky, Alexander D.; Levenson, Richard M.; Lowe, John B.; Liu, Scot D.; Zhao, Shuchun; Natkunam, Yasodha; Nolan, Garry P.

    2014-01-01

    Immunohistochemistry (IHC) is a tool for visualizing protein expression employed as part of the diagnostic work-up for the majority of solid tissue malignancies. Existing IHC methods use antibodies tagged with fluorophores or enzyme reporters that generate colored pigments. Because these reporters exhibit spectral and spatial overlap when used simultaneously, multiplexed IHC is not routinely used in clinical settings. We have developed a method that uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters. Multiplexed ion beam imaging (MIBI) is capable of analyzing up to 100 targets simultaneously over a five-log dynamic range. Here, we used MIBI to analyze formalin-fixed, paraffin-embedded (FFPE) human breast tumor tissue sections stained with ten labels simultaneously. The resulting data suggest that MIBI will provide new insights by integrating tissue microarchitecture with highly multiplexed protein expression patterns, and will be valuable for basic research, drug discovery and clinical diagnostics. PMID:24584119

  12. Assessment of breast tumor margins via quantitative diffuse reflectance imaging

    NASA Astrophysics Data System (ADS)

    Brown, J. Quincy; Bydlon, Torre M.; Kennedy, Stephanie A.; Geradts, Joseph; Wilke, Lee G.; Barry, William; Richards, Lisa M.; Junker, Marlee K.; Gallagher, Jennifer; Ramanujam, Nimmi

    2010-02-01

    A particular application of interest for tissue reflectance spectroscopy in the UV-Visible is intraoperative detection of residual cancer at the margins of excised breast tumors, which could prevent costly and unnecessary repeat surgeries. Our multi-disciplinary group has developed an optical imaging device, which is capable of surveying the entire specimen surface down to a depth of 1-2mm, all within a short time as required for intraoperative use. In an IRB-approved study, reflectance spectral images were acquired from 54 margins in 48 patients. Conversion of the spectral images to quantitative tissue parameter maps was facilitated by a fast scalable inverse Monte-Carlo model. Data from margin parameter images were reduced to image-descriptive scalar values and compared to gold-standard margin pathology. The utility of the device for classification of margins was determined via the use of a conditional inference tree modeling approach, and was assessed both as a function of type of disease present at the margin, as well as a function of distance of disease from the issue surface. Additionally, the influence of breast density on the diagnostic parameters, as well as the accuracy of the device, was evaluated.

  13. Malignant phyllodes tumor of the breast presenting with hypoglycemia: a case report and literature review

    PubMed Central

    Pacioles, Toni; Seth, Rahul; Orellana, Cesar; John, Ivy; Panuganty, Veera; Dhaliwal, Ruban

    2014-01-01

    Phyllodes tumors are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors and are typically found in middle-aged women. Phyllodes tumors that present with hypoglycemia are even rarer. No one morphologic finding is reliable in predicting the clinical behavior of this tumor. Surgery has been the primary mode of treatment to date. However, the extent of resection and the role of adjuvant radiotherapy or chemotherapy are still controversial. Here, we present a challenging case of malignant phyllodes tumor of the breast associated with hypoglycemia, and review the literature regarding clinical findings, pathologic risk factors for recurrence, and treatment recommendations. PMID:25525388

  14. Identification of Estrogen Response Element in Aquaporin-3 Gene that Mediates Estrogen-induced Cell Migration and Invasion in Estrogen Receptor-positive Breast Cancer

    PubMed Central

    Huang, Yi-Ting; Zhou, Jun; Shi, Shuai; Xu, Hai-Yan; Qu, Fan; Zhang, Dan; Chen, Yi-Ding; Yang, Jing; Huang, He-Feng; Sheng, Jian-Zhong

    2015-01-01

    Accumulating evidence suggests that aquaporins (AQPs) may facilitate tumor development. The molecular pathways connecting the pathological functions of AQPs are unclear and need to be better defined. This study aimed to investigate whether AQP3, one of the AQPs expressed highly in breast cancer, had any clinical implication in estrogen-receptor (ER) positive breast cancer, and explore the regulatory mechanisms of AQP3 in estrogen-related breast cancer progression. Here we show that AQP3 is an important enforcer of migration and invasion in breast cancer. We, for the first time, reported that ER-positive breast cancer tissues obtained from premenopausal patients had higher AQP3 expression when compared to those obtained from postmenopausal patients. Estrogen directly upregulates AQP3 by activating ERE in the promoter of the AQP3 gene. The upregulation of AQP3 can influence the expression of molecules related to epithelial-mesenchymal transition and the reorganization of actin-cytoskeleton, resulting in enhancement of cell migration and invasion in ER-positive breast cancer cells. PMID:26219409

  15. Even With Very Small Breast Tumors, Studies Find HER2 Status Matters | Division of Cancer Prevention

    Cancer.gov

    Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. |

  16. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients.

    PubMed

    Madic, Jordan; Kiialainen, Anna; Bidard, Francois-Clement; Birzele, Fabian; Ramey, Guillemette; Leroy, Quentin; Rio Frio, Thomas; Vaucher, Isabelle; Raynal, Virginie; Bernard, Virginie; Lermine, Alban; Clausen, Inga; Giroud, Nicolas; Schmucki, Roland; Milder, Maud; Horn, Carsten; Spleiss, Olivia; Lantz, Olivier; Stern, Marc-Henri; Pierga, Jean-Yves; Weisser, Martin; Lebofsky, Ronald

    2015-05-01

    Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome. PMID:25307450

  17. Time of flight estimation for breast cancer margin thickness using embedded tumors

    NASA Astrophysics Data System (ADS)

    Bowman, Tyler; El-Shenawee, Magda; Campbell, Lucas

    2016-03-01

    This work aims to enact a quick and reasonable estimation of breast cancer margin thickness using time of flight analysis of embedded breast cancer tissue. A pulsed terahertz system is used to obtain reflection imaging scans from breast cancer tumors that are formalin-fixed and embedded in paraffin blocks. Time of flight analysis is then used to compare the reflection patterns seen within the block to pathology sections and paraffin-embedded sections that are taken throughout the depth of the tumor in order to estimate the three-dimensional boundaries of the tumor.

  18. Protein tyrosine phosphatase receptor type O expression in the tumor niche correlates with reduced tumor growth, angiogenesis, circulating tumor cells and metastasis of breast cancer.

    PubMed

    Liu, Zhao; Hou, Jiajie; Ren, Lidong; He, Jing; Sun, Beicheng; Sun, Lu-Zhe; Wang, Shui

    2015-04-01

    Protein tyrosine phosphatase receptor type O (PTPRO) has been recognized as a tumor suppressor in various types of cancer cells. However, little attention has been given to the role of PTPRO expression in the tumor microenvironment. We aimed to reveal the role of PTPRO in the breast cancer niche. Py8119 mouse breast cancer cells were implanted orthotopically into female wild-type or ptpro-/- C57Bl/6 mice. We observed that the loss of PTPRO in the tumor niche was correlated with larger tumor volume, more metastases, increased number of circulating tumor cells (CTCs), less apoptosis and reduced necrosis rates in the orthotopic mouse model of breast cancer. The tumor microenvironment in the ptpro-/- mice also showed increased microvessel density. Moreover, an intracardiac injection mouse model was used to determine the role of PTPRO in the pre-metastatic niche. Notably, more metastases were observed in the mice of the ptpro-/- group. Taken together, PTPRO expression in the tumor niche prevents tumor growth and the formation of metastases of breast cancer, in part by attenuating tumor-associated angiogenesis and inducing the apoptosis and necrosis of tumor cells. PMID:25646811

  19. Tamoxifen Action in ER-Negative Breast Cancer

    PubMed Central

    Manna, Subrata; Holz, Marina K.

    2016-01-01

    Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER-positive breast cancers. Interestingly, 5–10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome. PMID:26989346

  20. Optical Spectral Surveillance of Breast Tissue Landscapes for Detection of Residual Disease in Breast Tumor Margins

    PubMed Central

    Kennedy, Stephanie A.; Caldwell, Matthew L.; Gallagher, Jennifer E.; Junker, Marlee; Wilke, Lee G.; Barry, William T.; Geradts, Joseph; Ramanujam, Nimmi

    2013-01-01

    We demonstrate a strategy to “sense” the micro-morphology of a breast tumor margin over a wide field of view by creating quantitative hyperspectral maps of the tissue optical properties (absorption and scattering), where each voxel can be deconstructed to provide information on the underlying histology. Information about the underlying tissue histology is encoded in the quantitative spectral information (in the visible wavelength range), and residual carcinoma is detected as a shift in the histological landscape to one with less fat and higher glandular content. To demonstrate this strategy, fully intact, fresh lumpectomy specimens (n = 88) from 70 patients were imaged intra-operatively. The ability of spectral imaging to sense changes in histology over large imaging areas was determined using inter-patient mammographic breast density (MBD) variation in cancer-free tissues as a model system. We discovered that increased MBD was associated with higher baseline β-carotene concentrations (p = 0.066) and higher scattering coefficients (p = 0.007) as measured by spectral imaging, and a trend toward decreased adipocyte size and increased adipocyte density as measured by histological examination in BMI-matched patients. The ability of spectral imaging to detect cancer intra-operatively was demonstrated when MBD-specific breast characteristics were considered. Specifically, the ratio of β-carotene concentration to the light scattering coefficient can report on the relative amount of fat to glandular density at the tissue surface to determine positive margin status, when baseline differences in these parameters between patients with low and high MBD are taken into account by the appropriate selection of threshold values. When MBD was included as a variable a priori, the device was estimated to have a sensitivity of 74% and a specificity of 86% in detecting close or positive margins, regardless of tumor type. Superior performance was demonstrated in high

  1. Pattern of Ipsilateral Breast Tumor Recurrence After Breast-Conserving Therapy

    SciTech Connect

    Jobsen, Jan; Palen, Job van der; Riemersma, Sietske; Heijmans, Harald; Ong, Francisca; Struikmans, Henk

    2014-08-01

    Purpose: To analyze the incidence and prognostic factors of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) in a large, population-based, single-center study with long-term follow-up. Methods and Materials: We analyzed 3595 cases in which BCT was performed in 3824 women with stage I or II breast cancer. The incidence of IBTR was analyzed over time and was based on IBTR as first event. Results: The 15-year local relapse-free survival was 90.9%. The hazard estimates for IBTR showed a time course with 2 peaks, the first at approximately 5 years and the second, twice as high, at 12 years. Stratifying subjects by age and margin status showed that, for women ≤40 years old with negative margins, adjuvant systemic therapy led to a 5-fold reduced risk of recurrence compared to none, and the presence of lymph vascular space invasion (LVSI) had a 3-fold increased risk compared to its absence. For women >40 years old, the presence of LVSI (hazard ratio [HR] 2.5) and the presence of lobular carcinoma in situ in the lumpectomy specimen (HR 2.3) were the only 2 risk factors. Conclusions: We demonstrated a pattern in risk of IBTR over time, with 2 peaks, first at approximately 5 years and a second, much higher peak at approximately 12 years, especially for women ≤40 years old. For women ≤40 years old with tumor-free resection margins, we noted that the absence of adjuvant systemic therapy and the presence of LVSI were independent prognostic factors of IBTR. For women >40 years old, the presence of LVSI and the presence of lobular carcinoma in situ were independent risk factors.

  2. Circulating tumor cells in breast cancer beyond the genotype of primary tumor for tailored therapy.

    PubMed

    Ren, Chuanli; Han, Chongxu; Fu, Deyuan; Wang, Daxin; Chen, Hui; Chen, Yong; Shen, Ming

    2016-04-01

    Although TNM staging based on tumor, node lymph status and metastasis status-is the most widely used method in the clinic to classify breast cancer (BC) and assess prognosis, it offers limited information for different BC subgroups. Circulating tumor cells (CTCs) are regarded as minimal residual disease and are proven to have a strong relationship with BC. Detection of ≥5 CTCs per 7.5 mL in peripheral blood predicts poor prognosis in metastatic BC irrespective of other clinical parameters, whereas, in early-stage BC, detection of CK19(+) CTCs are also associated with poor prognosis. Increasing data and clinical trials show that CTCs can improve prognostic accuracy and help tailor treatment for patients with BC. However, heterogeneous CTCs in the process of an epithelial-mesenchymal transition (EMT) in BC makes it a challenge to detect these rare cells. Moreover, the genotypic and phenotypic features of CTCs are different from primary BC tumors. Molecular analysis of CTCs in BC may benefit patients by identifying those amenable to tailored therapy. We propose that CTCs should be used alongside the TNM staging system and the genotype of primary tumor to guide tailored BC diagnosis and treatment. PMID:26178386

  3. VIS-NIR spectrum analysis for distinguishing tumor and normal human breast tissue

    NASA Astrophysics Data System (ADS)

    Zhang, Yang; Yu, Yuan; Tuchin, Valery V.; Chen, Yongjun; Wen, Xiang; Liu, Caihua; Wang, Jing; Xue, Xingbo; Zhu, Dan

    2012-03-01

    The high incidence and mortality of breast cancer require an effective method for early breast diagnosis. In order to investigate the optical differences among malignant tumor, benign tumor and normal human breast tissue, a commercial spectrophotometer combined with single integrating sphere was used to measure the optical properties of different types of breast tissue in the wavelength range of 400 nm to 2200 nm in vitro. The hematoxylin and eosin staining (H&E staining) are used as the standard, and to find the find possible optical markers from the corresponding absorption or scattering spectra. This work is not only used for in vitro rapid optical diagnosis, but very helpful to develop innovative optical diagnosis of breast tumor in vivo.

  4. Magnetoacoustic tomography with magnetic induction (MAT-MI) for breast tumor imaging: numerical modeling and simulation

    NASA Astrophysics Data System (ADS)

    Zhou, Lian; Li, Xu; Zhu, Shanan; He, Bin

    2011-04-01

    Magnetoacoustic tomography with magnetic induction (MAT-MI) was recently introduced as a noninvasive electrical conductivity imaging approach with high spatial resolution close to ultrasound imaging. In this study, we test the feasibility of the MAT-MI method for breast tumor imaging using numerical modeling and computer simulation. Using the finite element method, we have built three-dimensional numerical breast models with varieties of embedded tumors for this simulation study. In order to obtain an accurate and stable forward solution that does not have numerical errors caused by singular MAT-MI acoustic sources at conductivity boundaries, we first derive an integral forward method for calculating MAT-MI acoustic sources over the entire imaging volume. An inverse algorithm for reconstructing the MAT-MI acoustic source is also derived with spherical measurement aperture, which simulates a practical setup for breast imaging. With the numerical breast models, we have conducted computer simulations under different imaging parameter setups and all the results suggest that breast tumors that have large conductivity in contrast to the surrounding tissue as reported in the literature may be readily detected in the reconstructed MAT-MI images. In addition, our simulations also suggest that the sensitivity of imaging breast tumors using the presented MAT-MI setup depends more on the tumor location and the conductivity contrast between the tumor and its surrounding tissue than on the tumor size.

  5. Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts

    SciTech Connect

    Sambade, Maria J.; Kimple, Randall J.; Camp, J. Terese; Peters, Eldon; Livasy, Chad A.; Sartor, Carolyn I.; Shields, Janiel M.

    2010-06-01

    Purpose: To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. Methods and Materials: Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. Results: Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. Conclusion: Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.

  6. Lapatinib in Combination with Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts

    PubMed Central

    Sambade, Maria J.; Kimple, Randall J.; Camp, J. Terese; Peters, Eldon; Livasy, Chad A.; Sartor, Carolyn I.; Shields, Janiel M.

    2010-01-01

    Purpose To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. Methods and Materials Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. Results Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. Conclusion Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively. PMID:20457354

  7. Prognostic Impact of Time to Ipsilateral Breast Tumor Recurrence after Breast Conserving Surgery

    PubMed Central

    Gosset, Marie; Hamy, Anne-Sophie; Mallon, Peter; Delomenie, Myriam; Mouttet, Delphine; Pierga, Jean-Yves; Lae, Marick; Fourquet, Alain; Rouzier, Roman; Reyal, Fabien; Feron, Jean-Guillaume

    2016-01-01

    Background The poor prognosis of patients who experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is established. A short time between primary cancer and IBTR is a prognostic factor but no clinically relevant threshold was determined. Classification of IBTR may help tailor treatment strategies. Purpose We determined a specific time frame, which differentiates IBTR into early and late recurrence, and identified prognostic factors for patients with IBTR at time of the recurrence. Methods We analyzed 2209 patients with IBTR after BCS. We applied the optimal cut-points method for survival data to determine the cut-off times to IBTR. A subgroup analysis was performed by hormone receptor (HR) status. Survival analyses were performed using a Cox proportional hazard model to determine clinical features associated with distant-disease-free survival (DDFS) after IBTR. We therefor built decision trees. Results On the 828 metastatic events observed, the majority occurred within the first 3 months after IBTR: 157 in the HR positive group, 98 in the HR negative group. We found different prognostic times to IBTR: 49 months in the HR positive group, 33 in the HR negative group. After multivariate analysis, time to IBTR was the first discriminant prognostic factor in both groups (HR 0.65 CI95% [0.54–0.79] and 0.42 [0.30–0.57] respectively). The other following variables were significantly correlated with the DDFS: the initial number of positive lymph nodes for both groups, the initial tumor size and grade for HR positive tumors. Conclusion A short interval time to IBTR is the strongest factor of poor prognosis and reflects occult distant disease. It would appear that prognosis after IBTR depends more on clinical and histological parameters than on surgical treatment. A prospective trial in a low-risk group of patients to validate the safety of salvage BCS instead of mastectomy in IBTR is needed. PMID:27494111

  8. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

    PubMed Central

    TUOMELA, JOHANNA; SANDHOLM, JOUKO; KAUPPILA, JOONAS H.; LEHENKARI, PETRI; HARRIS, KEVIN W.; SELANDER, KATRI S.

    2013-01-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  9. Single Unpurified Breast Tumor-Initiating Cells from Multiple Mouse Models Efficiently Elicit Tumors in Immune-Competent Hosts

    PubMed Central

    Kurpios, Natasza A.; Girgis-Gabardo, Adele; Hallett, Robin M.; Rogers, Stephen; Gludish, David W.; Kockeritz, Lisa; Woodgett, James; Cardiff, Robert; Hassell, John A.

    2013-01-01

    The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tumors of several transgenic mouse models to determine their tumor-initiating cell frequency. We determined whether the tumors that formed following tumor cell transplantation phenocopied the primary tumors from which they were isolated and whether they could be serially transplanted. Finally we investigated whether propagating primary tumor cells in different tissue culture conditions affected their resident tumor-initiating cell frequency. We found that tumor-initiating cells comprised between 15% and 50% of the bulk tumor cell population in multiple independent mammary tumors from three different transgenic mouse models of breast cancer. Culture of primary mammary tumor cells in chemically-defined, serum-free medium as non-adherent tumorspheres preserved TIC frequency to levels similar to that of the primary tumors from which they were established. By contrast, propagating the primary tumor cells in serum-containing medium as adherent populations resulted in a several thousand-fold reduction in their tumor-initiating cell fraction. Our findings suggest that experimental conditions, including the sensitivity of the transplantation assay, can dramatically affect estimates of tumor initiating cell frequency. Moreover, conditional on cell culture conditions, the tumor-initiating cell fraction of bulk mouse mammary tumor cell preparations can either be maintained at high or low frequency in vitro thus permitting comparative studies of tumorigenic and non-tumorigenic cancer cells

  10. Tumoral Calcinosis: An Uncommon Cause for a Mass in a Reconstructed Breast

    PubMed Central

    Dean, Nicola R.; Watson, David I.; Carter, Christopher D.

    2016-01-01

    Summary: Tumoral calcinosis is a rare clinical and histopathological syndrome whose exact etiology is unknown. We present a case of a 57-year-old woman who presents with a painful lump in her right chest after bilateral breast reconstructions for bilateral asynchronous breast cancers. It is important to be aware of all possible differential diagnoses in a patient presenting with a chest mass after mastectomy and reconstruction for breast cancer as not all lesions of this type represent recurrent cancer.

  11. Tumoral Calcinosis: An Uncommon Cause for a Mass in a Reconstructed Breast.

    PubMed

    Koh, Eugene; Dean, Nicola R; Watson, David I; Carter, Christopher D

    2016-05-01

    Tumoral calcinosis is a rare clinical and histopathological syndrome whose exact etiology is unknown. We present a case of a 57-year-old woman who presents with a painful lump in her right chest after bilateral breast reconstructions for bilateral asynchronous breast cancers. It is important to be aware of all possible differential diagnoses in a patient presenting with a chest mass after mastectomy and reconstruction for breast cancer as not all lesions of this type represent recurrent cancer. PMID:27579225

  12. Locomotor proteins in tissues of primary tumors and metastases of ovarian and breast cancer

    NASA Astrophysics Data System (ADS)

    Kondakova, I. V.; Yunusova, N. V.; Spirina, L. V.; Shashova, E. E.; Kolegova, E. S.; Kolomiets, L. A.; Slonimskaya, E. M.; Villert, A. B.

    2016-08-01

    The paper discusses the capability for active movement in an extracellular matrix, wherein remodeling of the cytoskeleton by actin binding proteins plays a significant role in metastases formation. We studied the expression of actin binding proteins and β-catenin in tissues of primary tumors and metastases of ovarian and breast cancer. Contents of p45 Ser β-catenin and the actin severing protein gelsolin were decreased in metastases of ovarian cancer relative to primary tumors. The level of the cofilin, functionally similar to gelsolin, was significantly higher in metastases compared to primary ovarian and breast tumor tissue. In breast cancer, significant increase in the number of an actin monomer binder protein thymosin-β4 was observed in metastases as compared to primary tumors. The data obtained suggest the involvement of locomotor proteins in metastases formation in ovarian and breast cancer.

  13. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs.

    PubMed

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D

    2015-05-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies. PMID:26266007

  14. Thermal distribution analysis of three-dimensional tumor-embedded breast models with different breast density compositions.

    PubMed

    Wahab, Asnida Abd; Salim, Maheza Irna Mohamad; Ahamat, Mohamad Asmidzam; Manaf, Noraida Abd; Yunus, Jasmy; Lai, Khin Wee

    2016-09-01

    Breast cancer is the most common cancer among women globally, and the number of young women diagnosed with this disease is gradually increasing over the years. Mammography is the current gold-standard technique although it is known to be less sensitive in detecting tumors in woman with dense breast tissue. Detecting an early-stage tumor in young women is very crucial for better survival chance and treatment. The thermography technique has the capability to provide an additional functional information on physiological changes to mammography by describing thermal and vascular properties of the tissues. Studies on breast thermography have been carried out to improve the accuracy level of the thermography technique in various perspectives. However, the limitation of gathering women affected by cancer in different age groups had necessitated this comprehensive study which is aimed to investigate the effect of different density levels on the surface temperature distribution profile of the breast models. These models, namely extremely dense (ED), heterogeneously dense (HD), scattered fibroglandular (SF), and predominantly fatty (PF), with embedded tumors were developed using the finite element method. A conventional Pennes' bioheat model was used to perform the numerical simulation on different case studies, and the results obtained were then compared using a hypothesis statistical analysis method to the reference breast model developed previously. The results obtained show that ED, SF, and PF breast models had significant mean differences in surface temperature profile with a p value <0.025, while HD breast model data pair agreed with the null hypothesis formulated due to the comparable tissue composition percentage to the reference model. The findings suggested that various breast density levels should be considered as a contributing factor to the surface thermal distribution profile alteration in both breast cancer detection and analysis when using the thermography

  15. Local curvature analysis for classifying breast tumors: Preliminary analysis in dedicated breast CT

    PubMed Central

    Lee, Juhun; Nishikawa, Robert M.; Reiser, Ingrid; Boone, John M.; Lindfors, Karen K.

    2015-01-01

    Purpose: The purpose of this study is to measure the effectiveness of local curvature measures as novel image features for classifying breast tumors. Methods: A total of 119 breast lesions from 104 noncontrast dedicated breast computed tomography images of women were used in this study. Volumetric segmentation was done using a seed-based segmentation algorithm and then a triangulated surface was extracted from the resulting segmentation. Total, mean, and Gaussian curvatures were then computed. Normalized curvatures were used as classification features. In addition, traditional image features were also extracted and a forward feature selection scheme was used to select the optimal feature set. Logistic regression was used as a classifier and leave-one-out cross-validation was utilized to evaluate the classification performances of the features. The area under the receiver operating characteristic curve (AUC, area under curve) was used as a figure of merit. Results: Among curvature measures, the normalized total curvature (CT) showed the best classification performance (AUC of 0.74), while the others showed no classification power individually. Five traditional image features (two shape, two margin, and one texture descriptors) were selected via the feature selection scheme and its resulting classifier achieved an AUC of 0.83. Among those five features, the radial gradient index (RGI), which is a margin descriptor, showed the best classification performance (AUC of 0.73). A classifier combining RGI and CT yielded an AUC of 0.81, which showed similar performance (i.e., no statistically significant difference) to the classifier with the above five traditional image features. Additional comparisons in AUC values between classifiers using different combinations of traditional image features and CT were conducted. The results showed that CT was able to replace the other four image features for the classification task. Conclusions: The normalized curvature measure contains

  16. Production and characterization of monoclonal antibodies identifying breast tumor-associated antigens.

    PubMed Central

    Keydar, I; Chou, C S; Hareuveni, M; Tsarfaty, I; Sahar, E; Selzer, G; Chaitchik, S; Hizi, A

    1989-01-01

    We have generated a mouse monoclonal antibody (H23) against the retrovirus-like particles (human mammary tumor virus) released in vitro by the human breast adenocarcinoma cell line T47D. This antibody reacts specifically with a glycoprotein with an apparent molecular mass of 68 kDa (gp68) that is detected in the growth medium of T47D cells as well as in pleural effusion fluids from breast adenocarcinoma patients. No detectable levels of this antigen could be observed in pleural effusions of patients with cancers other than of breast origin. The H23-related antigen was localized in the cytoplasm of breast tumor cells as well as on the cell surface of both T47D cells and metastatic cells from breast cancer patients. A survey of tissue from 812 patients was performed by using H23 in an indirect immunoperoxidase assay. The results showed that the antigen was detectable in 91% of all breast tumors tested. No cytoplasmic staining was observed in either normal tissues or nonbreast carcinomas. Only one of the benign breast tissues tested (out of a total of 56 samples of tissue) was positive for this antigen. Given the ability of this antibody to specifically detect breast tumor cells, H23 may be of importance in diagnosis and in clinical follow-up of patients for the detection of metastatic lesions by imaging and for therapy. Images PMID:2465551

  17. Review: circulating tumor cells in the practice of breast cancer oncology.

    PubMed

    Ramos-Medina, R; Moreno, F; Lopez-Tarruella, S; Del Monte-Millán, M; Márquez-Rodas, I; Durán, E; Jerez, Y; Garcia-Saenz, J A; Ocaña, I; Andrés, S; Massarrah, T; González-Rivera, M; Martin, M

    2016-08-01

    The primary cause of tumor-related death in breast cancer is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. Circulating tumor cells (CTCs) play a major role in the metastatic spread of breast cancer. Different analytical systems for CTCs isolation and detection have been developed and novel areas of research are directed towards developing assays for CTCs molecular characterization. This review describes the current state of art on CTCs detection techniques and the present and future clinical implications of CTCs enumeration and characterization. PMID:26646763

  18. The stromal genome heterogeneity between breast and prostate tumors revealed by a comparative transcriptomic analysis.

    PubMed

    He, Kan; Lv, Wenwen; Zheng, Dongni; Cheng, Fei; Zhou, Tao; Ye, Shoudong; Ban, Qian; Ying, Qilong; Huang, Bei; Chen, Lei; Wu, Guohua; Liu, Dahai

    2015-04-20

    Stromal microenvironment increases tumor cell survival, proliferation and migration, and promotes angiogenesis. In order to provide comprehensive information on the stromal heterogeneity of diverse tumors, here we employed the microarray datasets of human invasive breast and prostate cancer-associated stromals and applied Gene Set Enrichment Analysis (GSEA) to compare the gene expression profiles between them. As a result, 8 up-regulated pathways and 73 down-regulated pathways were identified in the breast tumor stroma, while 32 up-regulated pathways and 18 down-regulated pathways were identified in the prostate tumor stroma. Only 9 pathways such as tryptophan metabolism were commonly up or down regulated, but most of them (including ABC transporters) were specific for these two tumors. Several essential tumors stromal marker genes were also significantly identified. For example, CDH3 was significantly up-regulated in the stromals of both breast and prostate tumors, however EGFR was only significantly down-regulated in the stromal of breast tumor. Our study would be helpful for future therapeutic and predictive applications in breast and prostate cancers. PMID:25826086

  19. Misdiagnosed male breast cancer with an unknown primary tumor: A case report

    PubMed Central

    WANG, WEN-WU; CHEN, LANG; OUYANG, XUE-NONG

    2014-01-01

    Compared with female breast cancer, male breast cancer (MBC) has an extremely low morbidity, later staging and fewer breast tissues. The lumps are easier to invade in the center and the majority of the cases are positive for metastatic lymph node, with the typical clinical manifestation as a painless mass in partial breast. MBC with an unknown primary tumor is rare and is often prone to misdiagnosis, resulting in a delay in correct treatment. Such a case is extremely significant for clinical reference. The current study presents a 58-year-old male who developed a painless mass in the left armpit and received armpit mass biopsy and pathological examination which showed glandular cancer, with a high possibility of mammary primary tumor. The patient was administered four cycles of paclitaxel plus oxaliplatin chemotherapy. However, three months later, the patient identified novel disseminated lymph nodes in the left armpit. The initial pathological section and paraffin blocks were re-examined and the patient was finally diagnosed with breast invasive ductal carcinoma based on the metastases pathology and immunohistochemical examination. No breast mass was found on physical examination of the patient and the tumor markers, including cancer antigen 125 and carcinoembryonic antigen, were normal. No primary tumors were observed in the mammography and PET-CT and the primary tumor was not found following the left breast modified radical mastectomy. PMID:24959243

  20. Performance analysis of a dedicated breast MR-HIFU system for tumor ablation in breast cancer patients

    NASA Astrophysics Data System (ADS)

    Deckers, R.; Merckel, L. G.; de Senneville, B. Denis; Schubert, G.; Köhler, M.; Knuttel, F. M.; Mali, W. P. Th M.; Moonen, C. T. W.; van den Bosch, M. A. A. J.; Bartels, L. W.

    2015-07-01

    MR-guided HIFU ablation is a promising technique for the non-invasive treatment of breast cancer. A phase I study was performed to assess the safety and treatment accuracy and precision of MR-HIFU ablation in breast cancer patients (n=10 ) using a newly developed MR-HIFU platform dedicated to applications in the breast. In this paper a technical analysis of the performance of the dedicated breast MR-HIFU system during breast tumors ablation is described. The main points of investigation were the spatial targeting accuracy and precision of the system and the performance of real-time respiration-corrected MR thermometry. The mean targeting accuracy was in the range of 2.4-2.6 mm, whereas the mean targeting precision was in the range of 1.5-1.8 mm. To correct for respiration-induced magnetic field fluctuations during MR temperature mapping a look-up-table (LUT)-based correction method was used. An optimized procedural sedation protocol in combination with the LUT-based correction method allowed for precise MR thermometry during the ablation procedure (temperature standard deviation <3 °C). No unwanted heating in the near field (i.e. skin) nor in the far field (pectoral muscle) was detected. The newly developed dedicated breast MR-HIFU system allows for safe, accurate and precise ablation of breast tumors.

  1. Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression.

    PubMed

    Welter, Michael; Fredrich, Thierry; Rinneberg, Herbert; Rieger, Heiko

    2016-01-01

    We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration

  2. Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression

    PubMed Central

    Welter, Michael; Fredrich, Thierry; Rinneberg, Herbert; Rieger, Heiko

    2016-01-01

    We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration

  3. Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer

    PubMed Central

    Lemort, Marc; Wilke, Celine; Vanderbeeken, Marie-Catherine; D’Hondt, Veronique; De Azambuja, Evandro; Gombos, Andrea; Lebrun, Fabienne; Dal Lago, Lissandra; Bustin, Fanny; Maetens, Marion; Ameye, Lieveke; Veys, Isabelle; Michiels, Stefan; Paesmans, Marianne; Larsimont, Denis; Sotiriou, Christos; Nogaret, Jean-Marie; Piccart, Martine; Awada, Ahmad

    2016-01-01

    Background EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. Methods HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. Results Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04). Conclusions The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment

  4. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    PubMed

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR. PMID:27216179

  5. Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer.

    PubMed

    Wang, Xuyi; Simpson, Evan R; Brown, Kristy A

    2015-09-01

    The number of breast cancer cases has increased in the last a few decades and this is believed to be associated with the increased prevalence of obesity worldwide. The risk of breast cancer increases with age beyond menopause and the relationship between obesity and the risk of breast cancer in postmenopausal women is well established. The majority of postmenopausal breast cancers are estrogen receptor (ER) positive and estrogens produced in the adipose tissue promotes tumor formation. Obesity results in the secretion of inflammatory factors that stimulate the expression of the aromatase enzyme, which converts androgens into estrogens in the adipose tissue. Evidence demonstrating a link between obesity and breast cancer has led to the investigation of metabolic pathways as novel regulators of estrogen production, including pathways that can be targeted to inhibit aromatase specifically within the breast. This review aims to present some of the key findings in this regard. PMID:26209254

  6. Effects of radiation on tumor hemodynamics and NF-kappaB in breast tumors

    NASA Astrophysics Data System (ADS)

    Stantz, Keith M.; Cao, Ning; Liu, Bo; Cao, Minsong; Chin-Sinex, Helen; Mendonca, Marc; Li, Jian Jian

    2010-02-01

    Purpose: The purpose of this study is to monitor in vivo the IR dose dependent response of NF-κB and tumor hemodynamics as a function of time. Material and Methods: An MDA-231 breast cancer cell line was stably transfected with a firefly luciferase gene within the NF-kappaB promoter. Tumors on the right flank irradiated with a single fractionated dose of 5Gy or 10Gy. Over two weeks, photoacoustic spectroscopy (PCT-S), bioluminescence imaging (BLI), and dynamic contrast enhanced CT (DCE-CT) was used to monitor hemoglobin status, NF-kappaB expression, and physiology, respectively. Results: From the BLI, an increase in NF-kappaB expression was observed in both the right (irradiation) and left (nonirradiated) tumors, which peaked at 8-12 hours, returned to basal levels after 24 hours, and increased a second time from 3 to 7 days. This data identifies both a radiation-induced bystander effect and a bimodal longitudinal response associated with NF-κB-controlled luciferase promoter. The physiological results from DCE-CT measured an increase in perfusion (26%) two days after radiation and both a decrease in perfusion and an increase in fp by week 1 (10Gy cohort). PCT-S measured increased levels of oxygen saturation two days post IR, which did not change after 1 week. Initially, NF-κB would modify hemodynamics to increase oxygen delivery after IR insult. The secondary response appears to modulate tumor angiogenesis. Conclusions: A bimodal response to radiation was detected with NF-kappaB-controlled luciferase reporter with a concomitant hemodynamic response associated with tumor hypoxia. Experiments are being performed to increase statistics.

  7. Epigenetic and genetic burden measures are associated with tumor characteristics in invasive breast carcinoma

    PubMed Central

    O'Sullivan, Dylan E.; Johnson, Kevin C.; Skinner, Lucy; Koestler, Devin C.; Christensen, Brock C.

    2016-01-01

    ABSTRACT The development and progression of invasive breast cancer is characterized by alterations to the genome and epigenome. However, the relationship between breast tumor characteristics, disease subtypes, and patient outcomes with the cumulative burden of these molecular alterations are not well characterized. We determined the average departure of tumor DNA methylation from adjacent normal breast DNA methylation using Illumina 450K methylation data from 700 invasive breast tumors and 90 adjacent normal breast tissues in The Cancer Genome Atlas. From this we generated a novel summary measure of altered DNA methylation, the DNA methylation dysregulation index (MDI), and examined the relation of MDI with tumor characteristics and summary measures that quantify cumulative burden of genetic mutation and copy number alterations. Our analysis revealed that MDI was significantly associated with tumor stage (P = 0.017). Across invasive breast tumor subtypes we observed significant differences in genome-wide DNA MDIs (P = 4.9E–09) and in a fraction of the genome with copy number alterations (FGA) (P = 4.6E–03). Results from a linear regression adjusted for subject age, tumor stage, and estimated tumor purity indicated a positive significant association of MDI with both MCB and FGA (P = 0.036 and P < 2.2E–16). A recursively partitioned mixture model of all 3 somatic alteration burden measures resulted in classes of tumors whose epigenetic and genetic burden profile were associated with the PAM50 subtype and mutations in TP53, PIK3CA, and CDH1. Together, our work presents a novel framework for characterizing the epigenetic burden and adds to the understanding of the aggregate impact of epigenetic and genetic alterations in breast cancer. PMID:27070496

  8. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice

    PubMed Central

    Esteva-Font, Cristina; Jin, Byung-Ju; Verkman, A. S.

    2014-01-01

    Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1+/+ MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm3 (se, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm3, 12 mice) were greatly reduced in AQP1−/− MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1−/− MMTV-PyVT mice, with reduced vessel density. HIF-1α expression was increased in tumors in AQP1−/− MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1+/+ MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.—Esteva-Font, C., Jin, B.-J., Verkman, A. S. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. PMID:24334548

  9. FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

    PubMed Central

    TAKENAKA, MIKI; SEKI, NAOKO; TOH, UHI; HATTORI, SATOSHI; KAWAHARA, AKIHIKO; YAMAGUCHI, TOMOHIKO; KOURA, KEIKO; TAKAHASHI, RYUJI; OTSUKA, HIROKO; TAKAHASHI, HIROKI; IWAKUMA, NOBUTAKA; NAKAGAWA, SHINO; FUJII, TERUHIKO; SASADA, TETSURO; YAMAGUCHI, RIN; YANO, HIROHISA; SHIROUZU, KAZUO; KAGE, MASAYOSHI

    2013-01-01

    The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3+ tumor cells and as being highly infiltrated by FOXP3+ lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3+ lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P<0.001), with a high infiltration of FOXP3+ lymphocytes accompanied by a cytoplasmic FOXP3+ tumor being the most detrimental phenotype. These findings indicated that FOXP3 expression in lymphocytes as well as in tumor cells may be a prognostic marker for breast cancer. FOXP3 in tumor cells may have distinct biological activities and prognostic values according to its localization, which may help establish appropriate cancer treatments. PMID:24649219

  10. Synchronous bilateral primary breast malignant phyllodes tumor and carcinoma of the breast with Paget’s disease: a case report and review of the literature

    PubMed Central

    Zhao, Hongyuan; Cheng, Xiaoming; Sun, Suhong; Yang, Weiming; Kong, Fanli; Zeng, Feng

    2015-01-01

    Synchronous bilateral primary breast malignant phyllodes tumor or/and carcinoma of the breast with Paget’s disease is rare. In the article, we present a case of bilateral carcinoma of the breast with Paget’s disease of the right breast and malignant phyllodes tumor of the left breast. A 44-years-old Chinese woman presented with a 1 month history of the right breast nipple with eczema and fester and growing and palpable mass of left breast. Molybdenum target X-ray revealed microcalcification in the right breast, which was highly suspected of malignant tumor, and round-like mass with smooth surface and homogeneous density in the left breast. Color ultrasound showed a lobulated lump which circumferential blood flows around in the left breast, and which did not show any mass in the right breast. The patient was undertaken the bilateral modified radical mastectomy. The histological diagnosis was Paget’s disease associated with infiltrating ductal carcinoma in the right breast and malignant phyllodes tumor the left breast. The patient also received 6 cycles of the postoperative adjuvant chemotherapy by using T.T. regimen comprised docetaxel (100 mg) and pirarubicin (60 mg). PMID:26770378

  11. Ductal carcinoma in situ in a benign phyllodes tumor of breast: A rare presentation.

    PubMed

    Ghosh, Prithwijit; Saha, Kaushik

    2014-07-01

    Phyllodes tumor (PT) is an uncommon tumor of female breast. The tumor clinically, radiologically, cytologically as well as histologically can mimic fibroadenoma which is a common tumor of fibroepithelial group. Ductal carcinoma in situ (DCIS) in the epithelial component of PT is very rare. We report a rare case of intermediate grade DCIS arising in a benign PT in a 42-year-old lady. The patient presented with a small nodule in right breast along with serosanguineous discharge from nipple. Ultrasonography and cytology failed to distinguish between fibroadenoma and PT. Histopathological examination following wide local excision displayed the biphasic tumor comprising of benign looking cellular stroma and epithelial lining. It also demonstrated the foci of intermediate grade DCIS without any invasive component. Considering the clinicoradiological profile along with histopathological features, the diagnosis of DCIS in a benign PT of breast was made. PMID:25097439

  12. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

    PubMed Central

    Bosch, Ana; Li, Zhiqiang; Bergamaschi, Anna; Ellis, Haley; Toska, Eneda; Prat, Aleix; Tao, Jessica J.; Spratt, Daniel E.; Viola-Villegas, Nerissa T.; Castel, Pau; Minuesa, Gerard; Morse, Natasha; Rodón, Jordi; Ibrahim, Yasir; Cortes, Javier; Perez-Garcia, Jose; Galvan, Patricia; Grueso, Judit; Guzman, Marta; Katzenellenbogen, John A.; Kharas, Michael; Lewis, Jason S.; Dickler, Maura; Serra, Violeta; Rosen, Neal; Chandarlapaty, Sarat; Scaltriti, Maurizio; Baselga, José

    2015-01-01

    Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective PI3Kα inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors, and that combined PI3K and ER inhibition is a rational approach to target these tumors. PMID:25877889

  13. Solitary fibrous tumor of the breast: a case report and review of the literature.

    PubMed

    Rhee, Sun Jung; Ryu, Jung Kyu; Han, Sang-Ah; Won, Kyu Yeoun

    2016-01-01

    Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that can be benign or malignant. SFTs have been most often documented in the pleura. Recently, involvement of extrapleural sites such as the abdomen, musculoskeletal soft tissue, upper respiratory tract, mediastinum, and head and neck were reported. Less than 15 cases of SFT of the breast have been reported. Here, we report a case of a pathologically proven SFT of the breast and review the literature on the radiologic findings. US imaging showed an oval, well-circumscribed, hypoechoic solid mass. A solitary fibrous tumor of the breast is a very rare lesion. PMID:26703178

  14. Breast tumor detection using UWB circular-SAR tomographic microwave imaging.

    PubMed

    Oloumi, Daniel; Boulanger, Pierre; Kordzadeh, Atefeh; Rambabu, Karumudi

    2015-08-01

    This paper describes the possibility of detecting tumors in human breast using ultra-wideband (UWB) circular synthetic aperture radar (CSAR). CSAR is a subset of SAR which is a radar imaging technique using a circular data acquisition pattern. Tomographic image reconstruction is done using a time domain global back projection technique adapted to CSAR. Experiments are conducted on a breast phantoms made of pork fat emulating normal and cancerous conditions. Preliminary experimental results show that microwave imaging of a breast phantom using UWB-CSAR is a simple and low-cost method, efficiently capable of detecting the presence of tumors. PMID:26737919

  15. Alcohol and breast cancer tumor subtypes in a Spanish Cohort.

    PubMed

    Gago-Dominguez, Manuela; Castelao, J Esteban; Gude, Francisco; Fernandez, Maite Peña; Aguado-Barrera, Miguel E; Ponte, Sara Miranda; Redondo, Carmen M; Castelo, Manuel Enguix; Dominguez, Alejandro Novo; Garzón, Víctor Muñoz; Carracedo, Angel; Martínez, María Elena

    2016-01-01

    Although alcohol intake is an established risk factor for overall breast cancer, few studies have looked at the relationship between alcohol use and breast cancer risk by the four major subtypes of breast cancer and very few data exist in the alcohol-breast cancer relationship in Spanish women. A population-based case-control study was conducted in Galicia, Spain. A total of 1766 women diagnosed with invasive breast cancer between 1997 and 2014 and 833 controls participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. We examined the alcohol-breast cancer association according to the major breast cancer subtypes [hormone-receptor-positive, HER2-negative (luminal A); hormone-receptor-positive, HER2-positive (luminal B); hormone-receptor-negative, HER2-negative (TNBC); and hormone-receptor-negative, HER2-positive (HER2 overexpressing)] as well as grade and morphology in Spanish women. With the exception of HER2 overexpressing, the risk of all subtypes of breast cancer significantly increased with increasing alcohol intake. The association was similar for hormonal receptor positive breast cancer, i.e., luminal A and luminal B breast cancer (odds ratio, OR 2.16, 95 % confidence interval, CI 1.55-3.02; and OR 1.98, 95 % CI 1.11-3.53, respectively), and for TNBC (TNBC: OR 1.93, 95 % CI 1.07-3.47). The alcohol-breast cancer association was slightly more pronounced among lobular breast cancer (OR 2.76, 95 % CI 1.62-4.69) than among ductal type breast cancers (OR 2.21, 95 % CI 1.61-3.03). In addition, significant associations were shown for all grades, I, II and III breast cancer (OR 1.98, 95 % CI 1.26-3.10; OR 2.34, 95 % CI 1.66-3.31; and OR 2.16, 95 % CI 1.44-3.25 for Grades I, II and III, respectively). To our knowledge, this is the first study to examine the association of breast cancer subtypes and alcohol intake in Spanish women. Our findings indicate that breast cancer risk increased

  16. Ipsilateral breast tumor recurrence after breast conservation therapy: Outcomes of salvage mastectomy vs. salvage breast-conserving surgery and prognostic factors for salvage breast preservation

    SciTech Connect

    Alpert, Tracy E.; Kuerer, Henry M.; Arthur, Douglas W.; Lannin, Donald R.; Haffty, Bruce G. . E-mail: hafftybg@umdnj.edu

    2005-11-01

    Purpose: To compare outcomes of salvage mastectomy (SM) and salvage breast-conserving surgery (SBCS) and study the feasibility of SBCS. Methods and Materials: Of 2,038 patients treated with breast-conserving therapy at Yale-New Haven Hospital before 1999, 166 sustained an ipsilateral breast tumor recurrence (IBTR). Outcomes and prognostic factors of patients treated with SM or SBCS were compared. Patients were considered amenable to SBCS if the recurrence was localized on mammogram and physical examination, and had pathologic size <3 cm, confined to the biopsy site, without skin or lymphovascular invasion, and with {<=}3 positive nodes. Results: Of the 146 patients definitively managed at IBTR, surgery was SM (n = 116) or SBCS (n 30). The median length of follow-up after IBTR was 13.8 years. The SM and SBCS cohorts had no significant differences, except at IBTR the SM cohort had a greater tumor size (p = 0.049). Of the SM cohort, 65.5% were considered appropriate for SBCS, and a localized relapse was predicted by estrogen-receptor positive, diploid, and detection of recurrence by mammogram. Multicentric disease correlated with BRCA1/2 mutation, estrogen-receptor negative, lymph node positive at relapse, and detection of recurrence by physical examination. Survival after IBTR was 64.5% at 10 years, with no significant difference between SM (65.7%) and SBCS (58.0%). Only 2 patients in the SBCS cohort subsequently had a second IBTR, and were salvaged with mastectomy. Conclusions: While mastectomy is considered the standard surgical salvage of IBTR, SBCS is feasible and prognostic factors are related to favorable tumor biology and early detection. Patients with BRCA1/2 germline mutations may be less appropriate for SBCS, as multicentric disease was more prevalent. Patients who underwent SBCS had comparable outcomes as those who underwent SM, but remain at continued risk for IBTR. A prospective trial evaluating repeat lumpectomy and partial breast reirradiation is

  17. Active adjoint modeling method in microwave induced thermoacoustic tomography for breast tumor.

    PubMed

    Zhu, Xiaozhang; Zhao, Zhiqin; Wang, Jinguo; Chen, Guoping; Liu, Qing Huo

    2014-07-01

    To improve the model-based inversion performance of microwave induced thermoacoustic tomography for breast tumor imaging, an active adjoint modeling (AAM) method is proposed. It aims to provide a more realistic breast acoustic model used for tumor inversion as the background by actively measuring and reconstructing the structural heterogeneity of human breast environment. It utilizes the reciprocity of acoustic sensors, and adapts the adjoint tomography method from seismic exploration. With the reconstructed acoustic model of breast environment, the performance of model-based inversion method such as time reversal mirror is improved significantly both in contrast and accuracy. To prove the advantage of AAM, a checkerboard pattern model and anatomical realistic breast models have been used in full wave numerical simulations. PMID:24956614

  18. A somatic truncating mutation in BRCA2 in a sporadic breast tumor

    SciTech Connect

    Weber, B.H.F.; Brohm, M.; Stec, I.

    1996-10-01

    Recently, a second susceptibility gene for hereditary breast and ovarian cancer, BRCA2, was cloned. The subsequent identification of heterozygous germ-line mutations confirmed its role as a predisposing factor in a subset of familial breast and ovarian cancer families. The possible involvement of BRCA2 in the sporadic forms of breast and ovarian tumors was addressed in three recent reports analyzing the gene for somatic mutations in 212 primary breast cancers and SS ovarian cancers. Although several alterations were identified, all except two changes were shown to represent germ-line mutations. Moreover, the two somatic BRCA2 alterations were found to be missense mutations resulting in a Asp309S-Glu change in one case and in a His2415Asn change in the other. Given the questionable effect of missense mutations on protein function, the role of BRCA2 in the carcinogenesis of sporadic breast tumors remains unclear. 10 refs., 1 fig.

  19. Tumor suppressor microRNAs: Targeted molecules and signaling pathways in breast cancer.

    PubMed

    Asghari, F; Haghnavaz, N; Baradaran, B; Hemmatzadeh, M; Kazemi, T

    2016-07-01

    Breast cancer is the most common type of cancer in women whose prevalence is increasing every year. Common strategies for diagnosis, prognosis and specific treatment of breast cancer need improvements to increase patients' survival. For this reason, there is growing number of efforts world-wide with molecular approaches. With the advent of microRNAs (miRNAs), they have been interested for almost all aspects of tumorgenesis and correlation of breast cancer and microRNAs was discovered for the first time in 2005. MiRNAs form a group of small noncoding RNAs which participate in regulation of gene expression and subsequently several biological processes and pathogenesis of various diseases. As other cancers, miRNAs involved in breast cancer are classified in two groups: the first group is tumor inducing miRNAs (also called oncomirs) that can induce tumor initiation and progression, and their expression is increased in cancerous cells. The second group is tumor suppressor miRNAs. In normal situation, tumor suppressor miRNAs prevent beginning and progression of breast cancer through suppressing the expression of various oncogenes. In this review we will give a general overview about miRNAs and breast cancer, and in the following, more discussion about tumor suppressor miRNAs, with focus on the best known of them and their targeted oncogenes and signaling pathways. Finally, we will point to application of this group of miRNAs in diagnosis, prognosis and treatment of patients. PMID:27261608

  20. Prone breast tumor imaging using vertical axis-of-rotation (VAOR) SPECT systems: An initial study

    SciTech Connect

    Wang, Huili; Scarfone, C.; Greer, K.L.; Coleman, R.E.

    1996-12-31

    We propose the use of a single photon emission computed tomography (SPECT) system equipped with multiple cameras revolving around a vertical axis-of-rotation (VAOR) to image tumors in a prone-dependent breast. This innovative breast imaging approach has the advantages of a small attenuation volume between breast lesions and gamma detector as well as a minimal radius-of-rotation compared to conventional (horizontal axis-of-rotation) breast SPECT. Small attenuation volume results in improved detected counts and minimal radius-of-rotation leads to increased collimator resolution. Because of no VAOR SPECT system currently available, we conducted our experiments on a conventional SPECT system using an isolated breast phantom to investigate the proposed VAOR breast SPECT. Our experimental setup simulated a VAOR SPECT study with a prone-dependent breast in the camera`s field-of-view. The results of our experiment indicate that VAOR breast SPECT with Trionix LESR parallel hole collimator is capable of detecting a breast lesion with a diameter of 10 mm and a lesion-to-background concentration ratio of 6 to 1. The results also demonstrate that VAOR breast SPECT provides improved lesion visualization over planar scintimammography and conventional breast SPECT.

  1. Asymmetric Cancer Hallmarks in Breast Tumors on Different Sides of the Body.

    PubMed

    Campoy, Emanuel M; Laurito, Sergio R; Branham, María T; Urrutia, Guillermo; Mathison, Angela; Gago, Francisco; Orozco, Javier; Urrutia, Raul; Mayorga, Luis S; Roqué, María

    2016-01-01

    During the last decades it has been established that breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH). The purpose of this study was to establish the methylation profile of CpG sites located in cancer genes in breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. For 51 breast carcinomas, MS-MLPA derived-methylation profiles of 81 CpG sites were converted into 6 CH profiles. CH profiles distribution was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised Hierarchical Cluster Analysis revealed that CH profiles segregate in two main groups (bootstrapping 90-100%), which correlate with breast laterality (p = 0.05). For validating these observations, gene expression data was obtained by RealTime-PCR in a different cohort of 25 tumors and converted into CH profiles. This analyses confirmed the same clustering and a tendency of association with breast laterality (p = 0.15). In silico analyses on gene expression data from TCGA Breast dataset from left and right breast tumors showed that they differed significantly when data was previously converted into CH profiles (p = 0.033). We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles. Our results indicate that by converting methylation or expression profiles in terms of Cancer Hallmarks, it would allow to uncover veiled associations with clinical features. These results contribute with a new finding to the better understanding of breast tumor behavior, and can moreover serve as proof of principle for other

  2. Asymmetric Cancer Hallmarks in Breast Tumors on Different Sides of the Body

    PubMed Central

    Campoy, Emanuel M.; Laurito, Sergio R.; Branham, María T.; Urrutia, Guillermo; Mathison, Angela; Gago, Francisco; Orozco, Javier; Urrutia, Raul; Mayorga, Luis S.; Roqué, María

    2016-01-01

    During the last decades it has been established that breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH). The purpose of this study was to establish the methylation profile of CpG sites located in cancer genes in breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. For 51 breast carcinomas, MS-MLPA derived-methylation profiles of 81 CpG sites were converted into 6 CH profiles. CH profiles distribution was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised Hierarchical Cluster Analysis revealed that CH profiles segregate in two main groups (bootstrapping 90–100%), which correlate with breast laterality (p = 0.05). For validating these observations, gene expression data was obtained by RealTime-PCR in a different cohort of 25 tumors and converted into CH profiles. This analyses confirmed the same clustering and a tendency of association with breast laterality (p = 0.15). In silico analyses on gene expression data from TCGA Breast dataset from left and right breast tumors showed that they differed significantly when data was previously converted into CH profiles (p = 0.033). We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles. Our results indicate that by converting methylation or expression profiles in terms of Cancer Hallmarks, it would allow to uncover veiled associations with clinical features. These results contribute with a new finding to the better understanding of breast tumor behavior, and can moreover serve as proof of principle for other

  3. Fibroblast Activation Protein Expression by Stromal Cells and Tumor-Associated Macrophages in Human Breast Cancer

    PubMed Central

    Julia, Tchou; Zhang Paul, J; Yingtao, Bi; Celine, Satija; Rajrupa, Marjumdar; Stephen, TL; Lo, A; Haiying, Chen; Carolyn, Mies; June, Carl H; Jose, Conejo-Garcia; Ellen, Puré

    2013-01-01

    Summary Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n=52) using a combination of immunostain analyses at the tissue and single cell level using freshly frozen or freshly digested human breast tumor samples respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP positive or FAP+ stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n=5), we demonstrated that some of these FAP+ CD45+ cells were CD11b+CD14+MHC-II+ indicating that they were likely tumor associated macrophages (TAMs). Although FAP+CD45+ cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP was novel and suggested that existing and future FAP directed therapy may have dual therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment. PMID:24074532

  4. Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors.

    PubMed

    Weitzenfeld, Polina; Kossover, Olga; Körner, Cindy; Meshel, Tsipi; Wiemann, Stefan; Seliktar, Dror; Legler, Daniel F; Ben-Baruch, Adit

    2016-06-01

    Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype. PMID:26936935

  5. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer

    PubMed Central

    2012-01-01

    Introduction Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer. Methods Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis. Results Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells

  6. Malignant phylloides tumor of breast in a pregnant woman with coincidental nulliparous vaginal prolapse.

    PubMed

    Ray, Sabyasachi; Basak, Subhadeep; Das, Subhabrata; Pal, Mallika; Konar, Hiralal

    2011-12-01

    Malignant phylloides tumor is a relatively rare and rapidly growing tumor of the breast. Presentation during pregnancy is uncommon. Reports regarding malignancy in these tumors differ greatly in incidence, and most of them are stromal malignancies. We report this case in which 24-year old primigravid patient in the 36(th) week of her pregnancy had a malignant phylloides tumor of breast with sudden growth and fine needle aspiration cytology of the breast was positive for malignancy. Ultimately after her caesarean delivery, excision biopsy was in favor of a malignant process. Pregnancy with nulliparous prolapse is also a rare condition. Those conditions are not associated with each other, but presence of two rare conditions in the same time in the same person is unique. PMID:23115419

  7. Malignant Phylloides Tumor of Breast in a Pregnant Woman with Coincidental Nulliparous Vaginal Prolapse

    PubMed Central

    Ray, Sabyasachi; Basak, Subhadeep; Das, Subhabrata; Pal, Mallika; Konar, Hiralal

    2011-01-01

    Malignant phylloides tumor is a relatively rare and rapidly growing tumor of the breast. Presentation during pregnancy is uncommon. Reports regarding malignancy in these tumors differ greatly in incidence, and most of them are stromal malignancies. We report this case in which 24-year old primigravid patient in the 36th week of her pregnancy had a malignant phylloides tumor of breast with sudden growth and fine needle aspiration cytology of the breast was positive for malignancy. Ultimately after her caesarean delivery, excision biopsy was in favor of a malignant process. Pregnancy with nulliparous prolapse is also a rare condition. Those conditions are not associated with each other, but presence of two rare conditions in the same time in the same person is unique. PMID:23115419

  8. Phyllodes Tumor of the Breast With Malignant Melanoma Component: A Case Report.

    PubMed

    Vergine, Marco; Guy, Catherine; Taylor, Mark R

    2015-09-01

    Phyllodes tumors of the breast display a wide variation in histological appearance and are classified into benign, borderline, and malignant categories based on a combination of histological parameters. These tumors may include a malignant heterologous component that is believed to originate through a process of multidirectional differentiation from a cancer stem cell. In these cases, the tumor is classified as a malignant phyllodes tumor. Among the heterologous elements that have been described in malignant phyllodes tumors are rhabdomyosarcoma, chondrosarcoma, osteosarcoma, liposarcoma and angiosarcoma. We present the first case of a phyllodes tumor with a malignant melanoma component in the breast of a 71-year-old lady, discussing the clinical implications of this diagnosis. PMID:26113664

  9. Reproductive Factors, Heterogeneity, and Breast Tumor Subtypes in Women of Mexican Descent

    PubMed Central

    Martinez, Maria Elena; Wertheim, Betsy C.; Natarajan, Loki; Schwab, Richard; Bondy, Melissa; Daneri-Navarro, Adrian; Meza-Montenegro, Maria Mercedes; Gutierrez-Millan, Luis Enrique; Brewster, Abenaa; Komenaka, Ian K.; Thompson, Patricia A.

    2013-01-01

    Background Published data support the presence of etiologic heterogeneity by breast tumor subtype, but few studies have assessed this in Hispanic populations. Methods We assessed tumor subtype prevalence and associations between reproductive factors and tumor subtypes in 1041 women of Mexican descent enrolled in a case-only, binational breast cancer study. Multinomial logistic regression comparing human epidermal growth factor receptor 2 positive (HER2+) tumors and triple negative breast cancer (TNBC) to luminal A tumors was conducted. Results Compared to women with luminal A tumors, those with a later age at first pregnancy were less likely to have TNBC (odds ratio [OR], 0.61; 95% CI, 0.39–0.95), whereas those with ≥ 3 full-term pregnancies were more likely to have TNBC (OR, 1.68; 95% CI, 1.10–2.55). A lower odds of TNBC was shown for longer menstruation duration, whether prior to first pregnancy (OR, 0.78; 95% CI, 0.65–0.93 per 10 years) or menopause (OR, 0.79; 95% CI, 0.69–0.91 per 10 years). Patients who reported breastfeeding for >12 months were over twice as likely to have TNBC than luminal A tumors (OR, 2.14; 95% CI, 1.24–3.68). Associations comparing HER2+ to luminal A tumors were weak or non-existent except for the interval between last full-term pregnancy and breast cancer diagnosis. Conclusions Findings show etiologic heterogeneity by tumor subtype in a population of Hispanic women with unique reproductive profiles. Impact Identification of etiologically distinct breast tumor subtypes can further improve our understanding of the disease and help provide personalized prevention and treatment regimens. PMID:23950213

  10. Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients

    PubMed Central

    Martin, Damali N.; Boersma, Brenda J.; Yi, Ming; Reimers, Mark; Howe, Tiffany M.; Yfantis, Harry G.; Tsai, Yien Che; Williams, Erica H.; Lee, Dong H.; Stephens, Robert M.; Weissman, Allan M.; Ambs, Stefan

    2009-01-01

    Background African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. Methods and Results Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-Americans was further investigated by examining the extent of vascularization and macrophage infiltration in an expanded set of 248 breast tumors. Immunohistochemistry revealed that microvessel density and macrophage infiltration is higher in tumors of African-Americans than in tumors of European-Americans. Lastly, using an in silico approach, we explored the potential of tailored treatment options for African-American patients based on their gene expression profile. This exploratory approach generated lists of therapeutics that may have specific antagonistic activity against tumors of African-American patients, e.g., sirolimus, resveratrol, and chlorpromazine in estrogen receptor-negative tumors. Conclusions The gene expression profiles of breast tumors indicate that differences in tumor biology may exist between African-American and European-American patients beyond the knowledge of current

  11. The Value of Tumor Infiltrating Lymphocytes (TILs) for Predicting Response to Neoadjuvant Chemotherapy in Breast Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Mao, Yan; Qu, Qing; Zhang, Yuzi; Liu, Junjun; Chen, Xiaosong; Shen, Kunwei

    2014-01-01

    Background We carried out a systematic review and meta-analysis to evaluate the predictive roles of tumor infiltrating lymphocytes (TILs) in response to neoadjuvant chemotherapy (NAC) in breast cancer. Method A PubMed and Web of Science literature search was designed. Random or fixed effect models were adopted to estimate the summary odds ratio (OR). Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. Publication bias was evaluated using a funnel plot, Egger's test and Begg's test. We included studies where the predictive significance of TILs, and/or TILs subset on the pathologic complete response (pCR) were determined in NAC of breast cancer. Results A total of 13 published studies (including 3251 patients) were eligible. In pooled analysis, the detection of higher TILs numbers in pre-treatment biopsy was correlated with better pCR to NAC (OR = 3.93, 95% CI, 3.26–4.73). Moreover, TILs predicted higher pCR rates in triple negative (OR = 2.49, 95% CI: 1.61–3.83), HER2 positive (OR = 5.05, 95% CI: 2.86–8.92) breast cancer, but not in estrogen receptor (ER) positive (OR = 6.21, 95%CI: 0.86–45.15) patients. In multivariate analysis, TILs were still an independent marker for high pCR rate (OR = 1.41, 95% CI: 1.19–1.66). For TILs subset, higher levels of CD8+ and FOXP3+ T-lymphocytes in pre-treatment biopsy respectively predicted better pathological response to NAC (OR = 6.44, 95% CI: 2.52–16.46; OR = 2.94, 95% CI: 1.05–8.26). Only FOXP3+ lymphocytes in post-NAC breast tissue were a predictive marker for low pCR rate in univariate (OR = 0.41, 95% CI: 0.21–0.80) and multivariate (OR = 0.36, 95% CI: 0.13–0.95) analysis. Conclusion Higher TILs levels in pre-treatment biopsy indicated higher pCR rates for NAC. TILs subset played different roles in predicting response to NAC. PMID:25501357

  12. Breast tumor characterization based on ultrawideband microwave backscatter.

    PubMed

    Davis, Shakti K; Van Veen, Barry D; Hagness, Susan C; Kelcz, Frederick

    2008-01-01

    Characterization of architectural tissue features such as the shape, margin, and size of a suspicious lesion is commonly performed in conjunction with medical imaging to provide clues about the nature of an abnormality. In this paper, we numerically investigate the feasibility of using multichannel microwave backscatter in the 1-11 GHz band to classify the salient features of a dielectric target. We consider targets with three shape characteristics: smooth, microlobulated, and spiculated; and four size categories ranging from 0.5 to 2 cm in diameter. The numerical target constructs are based on Gaussian random spheres allowing for moderate shape irregularities. We perform shape and size classification for a range of signal-to-noise ratios (SNRs) to demonstrate the potential for tumor characterization based on ultrawideband (UWB) microwave backscatter. We approach classification with two basis selection methods from the literature: local discriminant bases and principal component analysis. Using these methods, we construct linear classifiers where a subset of the bases expansion vectors are the input features and we evaluate the average rate of correct classification as a performance measure. We demonstrate that for 10 dB SNR, the target size is very reliably classified with over 97% accuracy averaged over 360 targets; target shape is classified with over 70% accuracy. The relationship between the SNR of the test data and classifier performance is also explored. The results of this study are very encouraging and suggest that both shape and size characteristics of a dielectric target can be classified directly from its UWB backscatter. Hence, characterization can easily be performed in conjunction with UWB radar-based breast cancer detection without requiring any special hardware or additional data collection. PMID:18232367

  13. Ultrashort Microwave-Pumped Real-Time Thermoacoustic Breast Tumor Imaging System.

    PubMed

    Ye, Fanghao; Ji, Zhong; Ding, Wenzheng; Lou, Cunguang; Yang, Sihua; Xing, Da

    2016-03-01

    We report the design of a real-time thermoacoustic (TA) scanner dedicated to imaging deep breast tumors and investigate its imaging performance. The TA imaging system is composed of an ultrashort microwave pulse generator and a ring transducer array with 384 elements. By vertically scanning the transducer array that encircles the breast phantom, we achieve real-time, 3D thermoacoustic imaging (TAI) with an imaging speed of 16.7 frames per second. The stability of the microwave energy and its distribution in the cling-skin acoustic coupling cup are measured. The results indicate that there is a nearly uniform electromagnetic field in each XY-imaging plane. Three plastic tubes filled with salt water are imaged dynamically to evaluate the real-time performance of our system, followed by 3D imaging of an excised breast tumor embedded in a breast phantom. Finally, to demonstrate the potential for clinical applications, the excised breast of a ewe embedded with an ex vivo human breast tumor is imaged clearly with a contrast of about 1:2.8. The high imaging speed, large field of view, and 3D imaging performance of our dedicated TAI system provide the potential for clinical routine breast screening. PMID:26552081

  14. CXM: a new tool for mapping breast cancer risk in the tumor microenvironment.

    PubMed

    Flister, Michael J; Endres, Bradley T; Rudemiller, Nathan; Sarkis, Allison B; Santarriaga, Stephanie; Roy, Ishan; Lemke, Angela; Geurts, Aron M; Moreno, Carol; Ran, Sophia; Tsaih, Shirng-Wern; De Pons, Jeffery; Carlson, Daniel F; Tan, Wenfang; Fahrenkrug, Scott C; Lazarova, Zelmira; Lazar, Jozef; North, Paula E; LaViolette, Peter S; Dwinell, Michael B; Shull, James D; Jacob, Howard J

    2014-11-15

    The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the nonmalignant microenvironment. Using CXM, we defined genetic variants on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3(IL2Rγ) consomic model compared with the SS(IL2Rγ) parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3(IL2Rγ) background. Through comparative mapping and whole-genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment that underlie differences in breast cancer risk. PMID:25172839

  15. Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo

    PubMed Central

    Lai, Priscilla; Tarapacki, Christine; Tran, William T.; El Kaffas, Ahmed; Lee, Justin; Hupple, Clinton; Iradji, Sarah; Giles, Anoja; Al-Mahrouki, Azza; Czarnota, Gregory J.

    2016-01-01

    Acoustically stimulated microbubbles have been demonstrated to perturb endothelial cells of the vasculature resulting in biological effects. In the present study, vascular and tumor response to ultrasound-stimulated microbubble and radiation treatment was investigated in vivo to identify effects on the blood vessel endothelium. Mice bearing breast cancer tumors (MDA-MB-231) were exposed to ultrasound after intravenous injection of microbubbles at different concentrations, and radiation at different doses (0, 2, and 8 Gy). Mice were sacrificed 12 and 24 hours after treatment for histopathological analysis. Tumor growth delay was assessed for up to 28 days after treatment. The results demonstrated additive antitumor and antivascular effects when ultrasound stimulated microbubbles were combined with radiation. Results indicated tumor cell apoptosis, vascular leakage, a decrease in tumor vasculature, a delay in tumor growth and an overall tumor disruption. When coupled with radiation, ultrasound-stimulated microbubbles elicited synergistic anti-tumor and antivascular effects by acting as a radioenhancing agent in breast tumor blood vessels. The present study demonstrates ultrasound driven microbubbles as a novel form of targeted antiangiogenic therapy in a breast cancer xenograft model that can potentiate additive effects to radiation in vivo. PMID:27226983

  16. Automated detection of breast tumor in MRI and comparison of kinetic features for assessing tumor response to chemotherapy

    NASA Astrophysics Data System (ADS)

    Aghaei, Faranak; Tan, Maxine; Zheng, Bin

    2015-03-01

    Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) is used increasingly in diagnosis of breast cancer and assessment of treatment efficacy in current clinical practice. The purpose of this preliminary study is to develop and test a new quantitative kinetic image feature analysis method and biomarker to predict response of breast cancer patients to neoadjuvant chemotherapy using breast MR images acquired before the chemotherapy. For this purpose, we developed a computer-aided detection scheme to automatically segment breast areas and tumors depicting on the sequentially scanned breast MR images. From a contrast-enhancement map generated by subtraction of two image sets scanned pre- and post-injection of contrast agent, our scheme computed 38 morphological and kinetic image features from both tumor and background parenchymal regions. We applied a number of statistical data analysis methods to identify effective image features in predicting response of the patients to the chemotherapy. Based on the performance assessment of individual features and their correlations, we applied a fusion method to generate a final image biomarker. A breast MR image dataset involving 68 patients was used in this study. Among them, 25 had complete response and 43 had partially response to the chemotherapy based on the RECIST guideline. Using this image feature fusion based biomarker, the area under a receiver operating characteristic curve is AUC = 0.850±0.047. This study demonstrated that a biomarker developed from the fusion of kinetic image features computed from breast MR images acquired pre-chemotherapy has potentially higher discriminatory power in predicting response of the patients to the chemotherapy.

  17. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status.

    PubMed

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors' ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  18. Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

    PubMed

    El-Boubbou, Kheireddine; Ali, Rizwan; Bahhari, Hassan M; AlSaad, Khaled O; Nehdi, Atef; Boudjelal, Mohamed; AlKushi, Abdulmohsen

    2016-06-15

    We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained. PMID:27269304

  19. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice.

    PubMed

    Vila-Leahey, Ava; Oldford, Sharon A; Marignani, Paola A; Wang, Jun; Haidl, Ian D; Marshall, Jean S

    2016-07-01

    Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1(-/-)/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

  20. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

    PubMed Central

    Vila-Leahey, Ava; Oldford, Sharon A.; Marignani, Paola A.; Wang, Jun; Haidl, Ian D.; Marshall, Jean S.

    2016-01-01

    ABSTRACT Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

  1. Meta analysis of efficacy and safety between Mammotome vacuum-assisted breast biopsy and open excision for benign breast tumor

    PubMed Central

    Ding, Boni; Chen, Daojin; Li, Xiaorong; Zhang, Hongyan

    2013-01-01

    Objective To compare the efficacy and safety between Mammotome vacuum-assisted breast biopsy (Mammotome VABB) and conventional open excision for benign breast tumor. Methods A computer-based online search of Medline, PubMed, Embase, Ovid, Cochrane Library, VIP, Wanfang, CNKI and Chinese Biological Medicine Database was performed, and conference references were manually searched. With the Cochrane Collaboration Guidelines, all randomized controlled trials comparing mammotome minimally invasive operation and conventional open excision were systematically reviewed. The Cochrane Collaboration’s RevMan 5.0 software was used for data analysis. Results A total of 15 studies involving 5,256 patients was included. Meta-analyses showed no significant difference in the size of tumor, postoperative hematomas, ecchymosis, ecchymoma and residual disease between Mammotome VABB and conventional open excision. Mammotome VABB was superior to open excision as to the size of incision, intraoperative blood loss, operative time, healing time, size of scar, wound infection and breast deformation. Conclusions Mammotome VABB is an ideal method for benign breast tumor. PMID:25083462

  2. Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

    PubMed Central

    Wang, Ze-Yu; Xing, Yun; Liu, Bin; Lu, Lei; Huang, Xiao; Ge, Chi-Yu; Yao, Wen-Jun; Xu, Mao-Lei; Gao, Zhen-Qiu; Cao, Rong-Yue; Wu, Jie; Li, Tai-Ming

    2012-01-01

    Cancer cell vaccine-based immunotherapy has received increasing interest in many clinical trials involving patients with breast cancer. Combining with appropriate adjuvants can enhance the weak immunogenic properties of tumor cell lysates (TCL). In this study, diphtheria toxin (DT) and two tandem repeats of mycobacterial heat shock protein 70 (mHSP70) fragment 407-426 (M2) were conjugated to TCL with glutaraldehyde, and the constructed cancer cell vaccine was named DT-TCL-M2. Subcutaneous injection of DT-TCL-M2 in mice effectively elicited tumor-specific polyclonal immune responses, including humoral and cellular immune responses. High levels of antibodies against TCL were detected in the serum of immunized mice with ELISA and verified with Western blot analyses. The splenocytes from immunized mice showed potent cytotoxicity on Ehrlich ascites carcinoma cells. Moreover, the protective antitumor immunity induced by DT-TCL-M2 inhibited tumor growth in a mouse breast tumor model. DT-TCL-M2 also attenuated tumor-induced angiogenesis and slowed tumor growth in a mouse intradermal tumor model. These findings demonstrate that TCL conjugated with appropriate adjuvants induced effective antitumor immunity in vivo. Improvements in potency could further make cancer cell vaccines a useful and safe method for preventing cancer recurrence after resection. PMID:22464650

  3. HYPOTHESIZED ROLE OF PREGNANCY HORMONES ON HER2+ BREAST TUMOR DEVELOPMENT

    PubMed Central

    Cruz, Giovanna I.; Martínez, María Elena; Natarajan, Loki; Wertheim, Betsy C.; Gago-Dominguez, Manuela; Bondy, Melissa; Daneri-Navarro, Adrian; Meza-Montenegro, María Mercedes; Gutierrez-Millan, Luis Enrique; Brewster, Abenaa; Schedin, Pepper; Komenaka, Ian K.; Castelao, J. Esteban; Carracedo, Angel; Redondo, Carmen M.; Thompson, Patricia A.

    2014-01-01

    Breast cancer incidence rates have declined among older but not younger women; the latter are more likely to be diagnosed with breast cancers carrying a poor prognosis. Epidemiological evidence supports an increase in breast cancer incidence following pregnancy with risk elevated as much as 10 years postpartum. We investigated the association between years since last full-term pregnancy at the time of diagnosis (≤10 or >10 years) and breast tumor subtype in a case series of premenopausal Hispanic women (n = 627). Participants were recruited in the United States, Mexico, and Spain. Cases with known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, with one or more full-term pregnancies ≥1 year prior to diagnosis were eligible for this analysis. Cases were classified into three tumor subtypes according to hormone receptor (HR+ = ER+ and/or PR+; HR− = ER− and PR−) expression and HER2 status: HR+/HER2−, HER2+ (regardless of HR), and triple negative breast cancer (TNBC). Case-only odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for HER2+ tumors in reference to HR+/HER2− tumors. Participants were pooled in a mixed-effects logistic regression model with years since pregnancy as a fixed effect and study site as a random effect. When compared to HR+/HER2− cases, women with HER2+ tumors were more likely be diagnosed in the postpartum period of ≤10 years (OR=1.68; 95% CI, 1.12–2.52). The effect was present across all source populations and independent of the HR status of the HER2+ tumor. Adjusting for age at diagnosis (≤45 or >45 years) did not materially alter our results (OR=1.78; 95% CI, 1.08–2.93). These findings support the novel hypothesis that factors associated with the postpartum breast, possibly hormonal, are involved in the development of HER2+ tumors. PMID:23135573

  4. β class II tubulin predominates in normal and tumor breast tissues

    PubMed Central

    Dozier, James H; Hiser, Laree; Davis, Jennifer A; Thomas, Nancy Stubbs; Tucci, Michelle A; Benghuzzi, Hamed A; Frankfurter, Anthony; Correia, John J; Lobert, Sharon

    2003-01-01

    Background Antimitotic chemotherapeutic agents target tubulin, the major protein in mitotic spindles. Tubulin isotype composition is thought to be both diagnostic of tumor progression and a determinant of the cellular response to chemotherapy. This implies that there is a difference in isotype composition between normal and tumor tissues. Methods To determine whether such a difference occurs in breast tissues, total tubulin was fractionated from lysates of paired normal and tumor breast tissues, and the amounts of β-tubulin classes I + IV, II, and III were measured by competitive enzyme-linked immunosorbent assay (ELISA). Only primary tumor tissues, before chemotherapy, were examined. Her2/neu protein amplification occurs in about 30% of breast tumors and is considered a marker for poor prognosis. To gain insight into whether tubulin isotype levels might be correlated with prognosis, ELISAs were used to quantify Her2/neu protein levels in these tissues. Results β-Tubulin isotype distributions in normal and tumor breast tissues were similar. The most abundant β-tubulin isotypes in these tissues were β-tubulin classes II and I + IV. Her2/neu levels in tumor tissues were 5–30-fold those in normal tissues, although there was no correlation between the Her2/neu biomarker and tubulin isotype levels. Conclusion These results suggest that tubulin isotype levels, alone or in combination with Her2/neu protein levels, might not be diagnostic of tumorigenesis in breast cancer. However, the presence of a broad distribution of these tubulin isotypes (for example, 40–75% β-tubulin class II) in breast tissue, in conjunction with other factors, might still be relevant to disease progression and cellular response to antimitotic drugs. PMID:12927047

  5. Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells.

    PubMed

    Niwa, Andressa Megumi; D Epiro, Gláucia Fernanda Rocha; Marques, Lilian Areal; Semprebon, Simone Cristine; Sartori, Daniele; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2016-06-01

    The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin. PMID:26932586

  6. Accelerated Partial Breast Irradiation through Brachytherapy for Ductal Carcinoma in situ: Factors Influencing Utilization and Risks of Second Breast Tumors

    PubMed Central

    Liu, Ying; Schloemann, Derek T.; Lian, Min; Colditz, Graham A.

    2015-01-01

    Purpose To examine influencing factors and outcomes of accelerated partial breast irradiation through brachytherapy (APBIb) versus whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). Patients and Methods From the Surveillance Epidemiology and End Results program, we identified 40749 women who were diagnosed with first primary DCIS between 2002 and 2011 and treated with breast conserving surgery (BCS) and radiotherapy. A multi-level logistic regression analysis was performed to estimate odds ratios of APBIb use. Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression. Results Overall, 2212 (4.5%) of 40749 women (the whole cohort) received APBIb. Factors associated with the increased use of APBIb included older age, non-Hispanic white race/ethnicity, smaller tumor size, hormone receptor positivity, comedo subtypes and urban residence. During the 46-month follow-up, 74 (0.8%) and 131 (1.4%) of 9165 propensity score-matched patients developed IBTs and CBTs, respectively. Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR, 1.74; 95% CI, 1.06 to 2.85) but not CBTs (OR, 0.91; 95% CI, 0.59 to 1.41). Conclusion This population-based study suggests that APBIb use for DCIS was influenced by patient and tumor characteristics as well as urbanization of residence. We observed a moderately increased IBT risk associated with APBIb versus WBI, suggesting that APBIb should be used with caution for DCIS before data from randomized controlled trials with long-term followups are available. PMID:25893591

  7. Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer

    PubMed Central

    Ahn, Sung Gwe; Jeong, Joon; Hong, SoonWon; Jung, Woo Hee

    2015-01-01

    With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer. PMID:26278518

  8. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications.

    PubMed

    Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

    2016-03-01

    Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer. PMID:26791754

  9. Ultrashort microwave pulsed thermoacoustic imaging for tumor localization over whole breast

    NASA Astrophysics Data System (ADS)

    Ji, Zhong; Fu, Yong; Lou, Cunguang

    2014-09-01

    Microwave-induced thermoacoustic imaging (TAI) has attracted considerable interest as a promising imaging modality. Previous studies show that TAI has great potential for use in breast tumor detection with high contrast and high spatial resolution, nevertheless it requires high energy density and possesses small field of view (FOV). In this paper, a ultrashort microwave pulse (USMP) TAI system was employed for quality imaging with much less energy density required , and simultaneously, large enough FOV was obtained to cover the whole breast. The experimental results clearly demonstrate that the new USMP TAI system can be used for three-dimensional (3-D) localization of deep breast tumors with low microwave radiation dose over the whole breast.

  10. The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway

    PubMed Central

    Salah, Zaidoun; Itzhaki, Ella; Aqeilan, Rami I

    2014-01-01

    The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway. PMID:25350971

  11. Genomic alterations of primary tumor and blood in invasive ductal carcinoma of breast

    PubMed Central

    2010-01-01

    Background Genomic alterations are important events in the origin and progression of various cancers, with DNA copy number changes associated with progression and treatment response in cancer. Array CGH is potentially useful in the identification of genomic alterations from primary tumor and blood in breast cancer patients. The aim of our study was to compare differences of DNA copy number changes in blood and tumor tissue in breast cancer. Methods DNA copy number changes in blood were compared to those in tumor tissue using array-comparative genomic hybridization in samples obtained from 30 breast cancer patients. The relative degree of chromosomal changes was analyzed using log2 ratios and data was validated by real-time polymerase chain reaction. Results Forty-six regions of gains present in more than 30% of the tissues and 70 regions of gains present in more than 30% of blood were identified. The most frequently gained region was chromosome 8q24. In total, agreement of DNA copy numbers between primary tumor and blood was minimal (Kappa = 0.138, p < 0.001). Conclusion Although there was only a slight agreement of DNA copy number alterations between the primary tumor and the blood samples, the blood cell copy number variation may have some clinical significance as compared to the primary tumor in IDC breast cancer patients. PMID:20409316

  12. Thermal analysis of induced damage to the healthy cell during RFA of breast tumor.

    PubMed

    Singh, Sundeep; Bhowmik, Arka; Repaka, Ramjee

    2016-05-01

    Effective pre-clinical computational modeling strategies have been demonstrated in this article to enable risk free clinical application of radiofrequency ablation (RFA) of breast tumor. The present study (a) determines various optimal regulating parameters required for RFA of tumor and (b) introduces an essential clinical monitoring scheme to minimize the extent of damage to the healthy cell during RFA of tumor. The therapeutic capabilities offered by RFA of breast tumor, viz., the rise in local temperature and induced thermal damage have been predicted by integrating the bioheat transfer model, the electric field distribution model and the thermal damage model. The mathematical model has been validated with the experimental results available in the literature. The results revealed that, the effective damage of tumor volume sparing healthy tissue essentially depends on the voltage, the exposure time, the local heat distribution, the tumor stage and the electrode geometric configuration. It has been confirmed that, the assessment of damage front can accurately determine the extent of damage as compared to the thermal front. The study further evaluates the damaged healthy and tumor volumes due to RFA of different stages of breast cancer. The assessment of cell survival and damage fractions discloses the propensity of reappearance/healing of tumor cells after treatment. PMID:27157337

  13. Mass spectrometry images acylcarnitines, phosphatidylcholines, and sphingomyelin in MDA-MB-231 breast tumor models.

    PubMed

    Chughtai, Kamila; Jiang, Lu; Greenwood, Tiffany R; Glunde, Kristine; Heeren, Ron M A

    2013-02-01

    The lipid compositions of different breast tumor microenvironments are largely unknown due to limitations in lipid imaging techniques. Imaging lipid distributions would enhance our understanding of processes occurring inside growing tumors, such as cancer cell proliferation, invasion, and metastasis. Recent developments in MALDI mass spectrometry imaging (MSI) enable rapid and specific detection of lipids directly from thin tissue sections. In this study, we performed multimodal imaging of acylcarnitines, phosphatidylcholines (PC), a lysophosphatidylcholine (LPC), and a sphingomyelin (SM) from different microenvironments of breast tumor xenograft models, which carried tdTomato red fluorescent protein as a hypoxia-response element-driven reporter gene. The MSI molecular lipid images revealed spatially heterogeneous lipid distributions within tumor tissue. Four of the most-abundant lipid species, namely PC(16:0/16:0), PC(16:0/18:1), PC(18:1/18:1), and PC(18:0/18:1), were localized in viable tumor regions, whereas LPC(16:0/0:0) was detected in necrotic tumor regions. We identified a heterogeneous distribution of palmitoylcarnitine, stearoylcarnitine, PC(16:0/22:1), and SM(d18:1/16:0) sodium adduct, which colocalized primarily with hypoxic tumor regions. For the first time, we have applied a multimodal imaging approach that has combined optical imaging and MALDI-MSI with ion mobility separation to spatially localize and structurally identify acylcarnitines and a variety of lipid species present in breast tumor xenograft models. PMID:22930811

  14. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast

    PubMed Central

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P.; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-01

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast. PMID:26625196

  15. Methylation profiling of 48 candidate genes in tumor and matched normal tissues from breast cancer patients.

    PubMed

    Li, Zibo; Guo, Xinwu; Wu, Yepeng; Li, Shengyun; Yan, Jinhua; Peng, Limin; Xiao, Zhi; Wang, Shouman; Deng, Zhongping; Dai, Lizhong; Yi, Wenjun; Xia, Kun; Tang, Lili; Wang, Jun

    2015-02-01

    Gene-specific methylation alterations in breast cancer have been suggested to occur early in tumorigenesis and have the potential to be used for early detection and prevention. The continuous increase in worldwide breast cancer incidences emphasizes the urgent need for identification of methylation biomarkers for early cancer detection and patient stratification. Using microfluidic PCR-based target enrichment and next-generation bisulfite sequencing technology, we analyzed methylation status of 48 candidate genes in paired tumor and normal tissues from 180 Chinese breast cancer patients. Analysis of the sequencing results showed 37 genes differentially methylated between tumor and matched normal tissues. Breast cancer samples with different clinicopathologic characteristics demonstrated distinct profiles of gene methylation. The methylation levels were significantly different between breast cancer subtypes, with basal-like and luminal B tumors having the lowest and the highest methylation levels, respectively. Six genes (ACADL, ADAMTSL1, CAV1, NPY, PTGS2, and RUNX3) showed significant differential methylation among the 4 breast cancer subtypes and also between the ER +/ER- tumors. Using unsupervised hierarchical clustering analysis, we identified a panel of 13 hypermethylated genes as candidate biomarkers that performed a high level of efficiency for cancer prediction. These 13 genes included CST6, DBC1, EGFR, GREM1, GSTP1, IGFBP3, PDGFRB, PPM1E, SFRP1, SFRP2, SOX17, TNFRSF10D, and WRN. Our results provide evidence that well-defined DNA methylation profiles enable breast cancer prediction and patient stratification. The novel gene panel might be a valuable biomarker for early detection of breast cancer. PMID:25636590

  16. Application of Protein Microarrays for Multiplexed Detection of Antibodies to Tumor Antigens in Breast Cancer

    PubMed Central

    Anderson, Karen S.; Ramachandran, Niroshan; Wong, Jessica; Raphael, Jacob V.; Hainsworth, Eugenie; Demirkan, Gokhan; Cramer, Daniel; Aronzon, Diana; Hodi, F. Stephen; Harris, Lyndsay; Logvinenko, Tanya; LaBaer, Joshua

    2012-01-01

    There is strong preclinical evidence that cancer, including breast cancer, undergoes immune surveillance. This continual monitoring, by both the innate and the adaptive immune systems, recognizes changes in protein expression, mutation, folding, glycosylation, and degradation. Local immune responses to tumor antigens are amplified in draining lymph nodes, and then enter the systemic circulation. The antibody response to tumor antigens, such as p53 protein, are robust, stable, and easily detected in serum, may exist in greater concentrations than their cognate antigens, and are potential highly specific biomarkers for cancer. However, antibodies have limited sensitivities as single analytes, and differences in protein purification and assay characteristics have limited their clinical application. For example, p53 autoantibodies in the sera are highly specific for cancer patients, but are only detected in the sera of 10-20% of patients with breast cancer. Detection of p53 autoantibodies is dependent on tumor burden, p53 mutation, rapidly decreases with effective therapy, but is relatively independent of breast cancer subtype. Although antibodies to hundreds of other tumor antigens have been identified in the sera of breast cancer patients, very little is known about the specificity and clinical impact of the antibody immune repertoire to breast cancer. Recent advances in proteomic technologies have the potential for rapid identification of immune response signatures for breast cancer diagnosis and monitoring. We have adapted programmable protein microarrays for the specific detection of autoantibodies in breast cancer. Here, we present the first demonstration of the application of programmable protein microarray ELISAs for the rapid identification of breast cancer autoantibodies. PMID:18311903

  17. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    SciTech Connect

    Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

    2013-08-02

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  18. Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

    PubMed Central

    Chang-Claude, Jenny; Goode, Ellen L.; Couch, Fergus J.; Nevanlinna, Heli; Milne, Roger L.; Gaudet, Mia; Schmidt, Marjanka K.; Broeks, Annegien; Cox, Angela; Fasching, Peter A.; Hein, Rebecca; Spurdle, Amanda B.; Blows, Fiona; Driver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomäki, Kristiina; Heikkilä, Päivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van ‘t Veer, Laura J.; van Leeuwen, Flora E.; Andrulis, Irene L.; Glendon, Gord; Knight, Julia A.; Mulligan, Anna Marie; O’Malley, Frances P.; Weerasooriya, Nayana; John, Esther M.; Beckmann, Matthias W.; Hartmann, Arndt; Weihbrecht, Sebastian B.; Wachter, David L.; Jud, Sebastian M.; Loehberg, Christian R.; Baglietto, Laura; English, Dallas R.; Giles, Graham G.; McLean, Catriona A.; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E.; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E.; Connley, Daniel; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.; Dörk, Thilo; Bremer, Michael; Meyer, Andreas; Karstens, Johann H.; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Pérez, Jose Ignacio; Rodríguez, Primitiva Menéndez; Zamora, Pilar; Benítez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Brüning, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M.; Tapper, William J.; Gerty, Sue M.; Sawyer, Elinor J.; Tomlinson, Ian P.; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Lindblom, Annika; Margolin, Sara; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Górski, Bohdan; Gronwald, Jacek; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Kriege, Mieke; Tilanus-Linthorst, Madeleine M. A.; Collée, Margriet; Wang-Gohrke, Shan; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Mononen, Kari; Grip, Mervi; Hirvikoski, Pasi; Winqvist, Robert; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Auvinen, Päivi; Soini, Ylermi; Sironen, Reijo; Bojesen, Stig E.; Dynnes Ørsted, David; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Børge G.; Holland, Helene; Chenevix-Trench, Georgia; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla; Sangrajrang, Suleeporn; Brennan, Paul; McKay, James; Odefrey, Fabrice; Gaborieau, Valerie; Devilee, Peter; Huijts, P.E.A.; Tollenaar, RAEM.; Seynaeve, C.; Dite, Gillian S.; Apicella, Carmel; Hopper, John L.; Hammet, Fleur; Tsimiklis, Helen; Smith, Letitia D.; Southey, Melissa C.; Humphreys, Manjeet K.; Easton, Douglas; Pharoah, Paul; Sherman, Mark E.; Garcia-Closas, Montserrat

    2011-01-01

    Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95

  19. Period-2: a tumor suppressor gene in breast cancer.

    PubMed

    Xiang, Shulin; Coffelt, Seth B; Mao, Lulu; Yuan, Lin; Cheng, Qi; Hill, Steven M

    2008-01-01

    Previous reports have suggested that the ablation of the Period 2 gene (Per 2) leads to enhanced development of lymphoma and leukemia in mice. Employing immunoblot analyses, we have demonstrated that PER 2 is endogenously expressed in human breast epithelial cell lines but is not expressed or is expressed at significantly reduced level in human breast cancer cell lines. Expression of PER 2 in MCF-7 breast cancer cells significantly inhibited the growth of MCF-7 human breast cancer cells, and, when PER 2 was co-expressed with the Crytochrome 2 (Cry 2) gene, an even greater growth-inhibitory effect was observed. The inhibitory effect of PER 2 on breast cancer cells was also demonstrated by its suppression of the anchorage-independent growth of MCF-7 cells as evidenced by the reduced number and size of colonies. A corresponding blockade of MCF-7 cells in the G1 phase of the cell cycle was also observed in response to the expression of PER 2 alone or in combination with CRY 2. Expression of PER 2 also induced apoptosis of MCF-7 breast cancer cells as demonstrated by an increase in PARP [poly (ADP-ribose) polymerase] cleavage. Finally, our studies demonstrate that PER 2 expression in MCF-7 breast cancer cells is associated with a significant decrease in the expression of cyclin D1 and an up-regulation of p53 levels. PMID:18334030

  20. Period-2: a tumor suppressor gene in breast cancer

    PubMed Central

    Xiang, Shulin; Coffelt, Seth B; Mao, Lulu; Yuan, Lin; Cheng, Qi; Hill, Steven M

    2008-01-01

    Previous reports have suggested that the ablation of the Period 2 gene (Per 2) leads to enhanced development of lymphoma and leukemia in mice. Employing immunoblot analyses, we have demonstrated that PER 2 is endogenously expressed in human breast epithelial cell lines but is not expressed or is expressed at significantly reduced level in human breast cancer cell lines. Expression of PER 2 in MCF-7 breast cancer cells significantly inhibited the growth of MCF-7 human breast cancer cells, and, when PER 2 was co-expressed with the Crytochrome 2 (Cry 2) gene, an even greater growth-inhibitory effect was observed. The inhibitory effect of PER 2 on breast cancer cells was also demonstrated by its suppression of the anchorage-independent growth of MCF-7 cells as evidenced by the reduced number and size of colonies. A corresponding blockade of MCF-7 cells in the G1 phase of the cell cycle was also observed in response to the expression of PER 2 alone or in combination with CRY 2. Expression of PER 2 also induced apoptosis of MCF-7 breast cancer cells as demonstrated by an increase in PARP [poly (ADP-ribose) polymerase] cleavage. Finally, our studies demonstrate that PER 2 expression in MCF-7 breast cancer cells is associated with a significant decrease in the expression of cyclin D1 and an up-regulation of p53 levels. PMID:18334030

  1. [INVITED] Time reversal optical tomography: Detecting and locating tumors in an ex vivo model human breast

    NASA Astrophysics Data System (ADS)

    Wu, Binlin; Alrubaiee, Mohammad; Gayen, S. K.

    2016-03-01

    Time reversal optical tomography (TROT), a recently introduced diffuse optical imaging approach, is used to detect, locate, and obtain cross-section images of tumors inside a "model human breast." The model cancerous breast is assembled as a semi-cylindrical slab of uniform thickness using ex vivo human breast tissues with two pieces of tumors embedded in it. The experimental arrangement used a 750-nm light beam from a Ti:sapphire laser to illuminate an end face (source plane) of the sample in a multi-source probing scheme. A multi-detector signal acquisition scheme measured transmitted light intensity distribution on the other end face (detector plane). The perturbations in light intensity distribution in the detector plane were analyzed using TROT to obtain locations of the tumor pieces in three dimensions and estimate their cross sections. The estimated locations and dimensions of targets are in good agreement with the results of a corroborating magnetic resonance imaging experiment.

  2. Microwave breast tumor detection and size estimation using contrast-agent-loaded magnetotactic bacteria.

    PubMed

    Chen, Yifan; Kosmas, Panagiotis; Martel, Sylvain

    2013-01-01

    We propose a new approach to microwave breast tumor detection based on the use of bio-compatible flagellated magnetotactic bacteria (MTB). Previous work has shown that the directions and speeds of these bacterial microrobots adapted to operate in human microvasculature can be guided along preplanned paths deep inside the human body through external magnetic fields. Furthermore, a microwave contrast agent can be loaded onto MTB to alter the dielectric properties of tissues near the agent. Based on these two phenomena, we illustrate how multiple agglomerations of MTB released into human breast could be tracked simultaneously and monitored using differential microwave imaging (DMI) techniques. We also present novel strategies to detect and localize a breast cancerous mass as well as estimate its size through this new DMI-trackable bacterial propulsion and steering approach, and use an anatomically realistic breast model as a testbed to verify the feasibility of this breast cancer diagnostic technique. PMID:24110977

  3. Observation of tumor microvessels that are controlled by blood flow in breast cancer

    NASA Astrophysics Data System (ADS)

    Ishida, H.; Andoh, T.; Akiguchi, S.; Kyoden, T.; Hachiga, T.

    2015-04-01

    We attempted to perform non-invasive breast cancer imaging using a reflection-type multipoint laser Doppler velocimeter to monitor blood flow. On day six, after transplantation of cancer cells into mouse breast, we found that blood flow velocity in a blood vessel that extended into the tumor was increased compared to that in normal skin. The effect of carcinogenesis on blood flow over such a short period was shown using blood flow velocity imaging. Although such imaging has not yet been adapted for use in humans, this study is an important step in reaching the ultimate goal, which is early detection of breast cancer.

  4. Dopamine receptor antagonist thioridazine inhibits tumor growth in a murine breast cancer model.

    PubMed

    Yin, Tao; He, Sisi; Shen, Guobo; Ye, Tinghong; Guo, Fuchun; Wang, Yongsheng

    2015-09-01

    Neuropsychological factors have been shown to influence tumor progression and therapeutic response. The present study investigated the effect of the dopamine receptor antagonist thioridazine on murine breast cancer. The anti‑tumor efficacy of thioridazine was assessed using a murine breast cancer model. Cell apoptosis and proliferation were analyzed in vitro using flow cytometry (FCM) and the MTT assay, respectively. Western blot analysis was performed to assess Akt, phosphorylated (p)‑Akt, signal transducer and activator of transcription (STAT) 3, p‑STAT3 and p‑p65 in tumor cells following treatment with thioridazine. The Ki67 index and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)‑positive apoptotic cells were assessed in the tumor sections. Thioridazine was found to reduce tumor growth, inhibit tumor cell proliferation and induce apoptosis in a dose‑ and time‑dependent manner in vitro. Thioridazine was also found to markedly inhibit tumor proliferation and induce tumor cell apoptosis in vivo as shown by the lower Ki67 index and increase in TUNEL‑positive cells. In addition, thioridazine was observed to inhibit the activation of the canonical nuclear factor κ‑light‑chain‑enhancer of activated B cells pathway and exert anti‑tumor effects by remodeling the tumor stroma, as well as inhibit angiogenesis in the tumor microenvironment. In conclusion, thioridazine was found to significantly inhibit breast tumor growth and the potential for thioridazine to be used in cancer therapy may be re‑evaluated and investigated in clinical settings. PMID:26095429

  5. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

    SciTech Connect

    Singh, Bhupendra; Mense, Sarah M.; Bhat, Nimee K.; Putty, Sandeep; Guthiel, William A.; Remotti, Fabrizio; Bhat, Hari K.

    2010-09-01

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17{beta}-estradiol (E{sub 2}). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E{sub 2}-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E{sub 2} pellets, co-exposure to quercetin did not protect rats from E{sub 2}-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E{sub 2}-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E{sub 2} group relative to those in the E{sub 2} group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F{sub 2{alpha}} (8-iso-PGF{sub 2{alpha}}) levels as a marker of oxidant stress showed that quercetin did not decrease E{sub 2}-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E{sub 2}-induced oxidant stress and may exacerbate breast carcinogenesis in E{sub 2}-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E{sub 2} and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E{sub 2} and chronic exposure to oxidant stress as a result of metabolic redox

  6. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting

    PubMed Central

    García-Teijido, Paula; Cabal, María Luque; Fernández, Ignacio Peláez; Pérez, Yolanda Fernández

    2016-01-01

    Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials. PMID:27081325

  7. Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes.

    PubMed

    Purrington, Kristen S; Visscher, Daniel W; Wang, Chen; Yannoukakos, Drakoulis; Hamann, Ute; Nevanlinna, Heli; Cox, Angela; Giles, Graham G; Eckel-Passow, Jeanette E; Lakis, Sotiris; Kotoula, Vassiliki; Fountzilas, George; Kabisch, Maria; Rüdiger, Thomas; Heikkilä, Päivi; Blomqvist, Carl; Cross, Simon S; Southey, Melissa C; Olson, Janet E; Gilbert, Judy; Deming-Halverson, Sandra; Kosma, Veli-Matti; Clarke, Christine; Scott, Rodney; Jones, J Louise; Zheng, Wei; Mannermaa, Arto; Eccles, Diana M; Vachon, Celine M; Couch, Fergus J

    2016-05-01

    Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified. PMID:27083182

  8. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature.

    PubMed

    Miao, Zhenhua; Luker, Kathryn E; Summers, Bretton C; Berahovich, Rob; Bhojani, Mahaveer S; Rehemtulla, Alnawaz; Kleer, Celina G; Essner, Jeffrey J; Nasevicius, Aidas; Luker, Gary D; Howard, Maureen C; Schall, Thomas J

    2007-10-01

    Chemokines and chemokine receptors have been posited to have important roles in several common malignancies, including breast and lung cancer. Here, we demonstrate that CXCR7 (RDC1, CCX-CKR2), recently deorphanized as a chemokine receptor that binds chemokines CXCL11 and CXCL12, can regulate these two common malignancies. Using a combination of overexpression and RNA interference, we establish that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. Furthermore, immunohistochemistry of primary human tumor tissue demonstrates extensive CXCR7 expression in human breast and lung cancers, where it is highly expressed on a majority of tumor-associated blood vessels and malignant cells but not expressed on normal vasculature. In addition, a critical role for CXCR7 in vascular formation and angiogenesis during development is demonstrated by using morpholino-mediated knockdown of CXCR7 in zebrafish. Taken together, these data suggest that CXCR7 has key functions in promoting tumor development and progression. PMID:17898181

  9. Phylloides Tumor With Numerous Thanatosomes ("Death Bodies"): A Report of Two Cases and a Study of Thanatosomes in Breast Tumors.

    PubMed

    D'Alfonso, Timothy M; Ginter, Paula S; Salvatore, Steven P; Antonio, Lilian B; Hoda, Syed A

    2014-06-01

    Thanatosomes, a form of degenerative intracellular hyaline globules, have been described in various neoplastic and nonneoplastic disease processes in several organs. These structures are indicative of apoptotic cell death. Herein, we report 2 cases of malignant phylloides tumor, both of which showed numerous thanatosomes-to the point of dominating the histological appearance and masking the stromal element. Our subsequently conducted study showed that thanatosomes were present in 14 of 86 (16.3%) high-grade malignant breast tumors. The structures were identified in 5/25 (20%) malignant phylloides tumors, 4/19 (21.1%) metaplastic spindle cell carcinomas, 3/21 (14.3%) invasive carcinomas s/p neoadjuvant chemotherapy, and 2/21 (9.5%) poorly differentiated invasive ductal carcinomas. When present, thanatosomes were typically a rare and focal finding in most types of cases. In malignant phylloides tumors, the structures were relatively more numerous when present. Our study shows that although thanatosomes can be present in several types of malignant breast tumors, they are more common in malignant phylloides tumor. Only rarely, as evident from our 2 index cases, do thanatosomes cause diagnostic difficulty. PMID:23564701

  10. Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors

    PubMed Central

    Abe, Shinya; Yamamoto, Kouhei; Kurata, Morito; Abe-Suzuki, Shiho; Horii, Rie; Akiyama, Futoshi; Kitagawa, Masanobu

    2015-01-01

    Highly malignant tumors express high levels of the minichromosome maintenance 2 (MCM2) protein, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound MCM2, impaired its nuclear translocation, and enhanced DNA-damage-induced apoptosis in FLV-infected hematopoietic cells when the cells expressed high levels of MCM2. Here, we show that MCM2 is highly expressed in clinical samples of invasive carcinoma of the breast, especially triple-negative breast cancer (TNBC), and in cancer stem cell (CSC) marker-positive breast cancer cells. To generate a cancer therapy model using gp70, we introduced the gp70 protein into the cytoplasm of murine breast cancer cells that express high levels of MCM2 by conjugating the protein transduction domain (PTD) of Hph-1 to gp70 (Hph- 1-gp70). Hph-1-gp70 was successfully transduced into the cytoplasm of breast cancer cells. The transduced protein enhanced the DNA damage-induced apoptosis of cancer cells in vitro and in vivo. Therefore, an MCM2-targeted strategy using Hph-1-gp70 treatment to induce DNA damage might be a successful therapy for highly malignant breast cancers such as TNBC and for the eradication of CSC-like cells from breast cancer tissue. PMID:26430873

  11. Frequent promoter hypermethylation and expression reduction of the glucocorticoid receptor gene in breast tumors

    PubMed Central

    Nesset, Kirsten A; Perri, Ami M; Mueller, Christopher R

    2014-01-01

    Previous studies have found that expression of the Glucocorticoid Receptor (GR) is altered or reduced in various cancers, while the GR promoter has been shown to be methylated in gastric, lung, and colorectal cancers. Examining a small cohort of matched normal and breast cancer samples we found that GR levels were dramatically reduced in almost all tumors in relation to their normal tissue. The methylation status of the GR promoter was assessed to determine if this observed decrease of expression in breast tumors could be due to epigenetic regulation. While it was not methylated in normal tissue, the GR proximal promoter was methylated in 15% of tumor samples, particularly, but not exclusively, in Estrogen Receptor positive tumors. GR expression in these tumors was particularly low and loss of GR expression was specifically correlated with methylation of the proximal promoter GR B region. Overall, these results show that hypermethylation of the promoter in tumors is a frequent event and suggests that GR may act as a tumor suppressor in breast tissue. PMID:24622770

  12. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  13. Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.

    PubMed

    Al Marzouqi, Nadia; Iratni, Rabah; Nemmar, Abderrahim; Arafat, Kholoud; Ahmed Al Sultan, Mahmood; Yasin, Javed; Collin, Peter; Mester, Jan; Adrian, Thomas E; Attoub, Samir

    2011-10-01

    Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 μM) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 μM at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 μM at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 μg/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer. PMID:21741966

  14. Breast tumor segmentation in high resolution x-ray phase contrast analyzer based computed tomography

    SciTech Connect

    Brun, E.; Grandl, S.; Sztrókay-Gaul, A.; Gasilov, S.; Barbone, G.; Mittone, A.; Coan, P.; Bravin, A.

    2014-11-01

    Purpose: Phase contrast computed tomography has emerged as an imaging method, which is able to outperform present day clinical mammography in breast tumor visualization while maintaining an equivalent average dose. To this day, no segmentation technique takes into account the specificity of the phase contrast signal. In this study, the authors propose a new mathematical framework for human-guided breast tumor segmentation. This method has been applied to high-resolution images of excised human organs, each of several gigabytes. Methods: The authors present a segmentation procedure based on the viscous watershed transform and demonstrate the efficacy of this method on analyzer based phase contrast images. The segmentation of tumors inside two full human breasts is then shown as an example of this procedure’s possible applications. Results: A correct and precise identification of the tumor boundaries was obtained and confirmed by manual contouring performed independently by four experienced radiologists. Conclusions: The authors demonstrate that applying the watershed viscous transform allows them to perform the segmentation of tumors in high-resolution x-ray analyzer based phase contrast breast computed tomography images. Combining the additional information provided by the segmentation procedure with the already high definition of morphological details and tissue boundaries offered by phase contrast imaging techniques, will represent a valuable multistep procedure to be used in future medical diagnostic applications.

  15. Stromal Activation by Tumor Cells: An in Vitro Study in Breast Cancer

    PubMed Central

    Merlino, Giuseppe; Miodini, Patrizia; Paolini, Biagio; Carcangiu, Maria Luisa; Gennaro, Massimiliano; Dugo, Matteo; Daidone, Maria Grazia; Cappelletti, Vera

    2016-01-01

    Background: The tumor microenvironment participates in the regulation of tumor progression and influences treatment sensitivity. In breast cancer, it also may play a role in determining the fate of non-invasive lesions such as ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive diseases, which is aggressively treated despite its indolent nature in many patients since no biomarkers are available to predict the progression of DCIS to invasive disease. In vitro models of stromal activation by breast tumor cells might provide clues as to specific stromal genes crucial for the transition from DCIS to invasive disease. Methods: normal human dermal fibroblasts (NHDF) were treated under serum-free conditions with cell culture media conditioned by breast cancer cell lines (SkBr3, MDA-MB-468, T47D) for 72 h and subjected to gene expression profiling with Illumina platform. Results: TGM2, coding for a tissue transglutaminase, was identified as candidate gene for stromal activation. In public transcriptomic datasets of invasive breast tumors TGM2 expression proved to provide prognostic information. Conversely, its role as an early biosensor of tumor invasiveness needs to be further investigated by in situ analyses. Conclusion: Stromal TGM2 might probably be associated with precancerous evolution at earlier stages compared to DCIS. PMID:27600076

  16. Evaluating mononuclear cells as nanoparticle delivery vehicles for the treatment of breast tumors

    NASA Astrophysics Data System (ADS)

    Murton, Jaclyn K.; Hu, Chelin; Ahmed, Mona M.; Hathaway, Helen J.; Nysus, Monique; Anderson Daniels, Tamara; Norenberg, Jeffrey P.; Adolphi, Natalie L.

    2015-08-01

    In breast cancer, certain types of circulating immune cells respond to long-range chemical signals from tumors by leaving the blood stream to actively infiltrate tumor tissue. The aim of this study was to evaluate whether immune cells could be used to deliver therapeutic nanoparticles into breast tumors in mice. Mononuclear splenocytes (MS) were harvested from donor mice, labeled with Indium-111, injected intravenously into immune-competent recipient mice (3 tumor-bearing and 3 control), and imaged longitudinally by SPECT/CT. For comparison, the biodistribution of bonemarrow derived macrophages (BMDM) in one pair of mice was also imaged. Quantitative analysis of the SPECT images demonstrates that, after 24 hours, the concentration of MS detected in mammary tumors is more than 3-fold higher than the concentration detected in normal mammary glands. The ratio of MS concentration in mammary tissue to MS concentration in non-target tissues (muscle, lung, heart, liver, spleen, and kidney) was enhanced in tumor-bearing mice (compared to controls), with statistical significance achieved for mammary/muscle (p<0.01), mammary/lung (p<0.05), and mammary/kidney (p<0.05). By contrast, BMDM did not show a different affinity for tumors relative to normal mammary tissue. MS were incubated with 100 nm red fluorescent nanoparticles, and flow cytometry demonstrated that ~35% of the MS population exhibited strong phagocytic uptake of the nanoparticles. After intravenous injection into tumor-bearing mice, fluorescence microscopy images of tumor sections show qualitatively that nanoparticle-loaded MS retain the ability to infiltrate mammary tumors. Taken together, these results suggest that MS carriers are capable of actively targeting therapeutic nanoparticles to breast tumors.

  17. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    PubMed

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  18. Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer

    PubMed Central

    Fackler, Mary Jo; Bujanda, Zoila Lopez; Umbricht, Christopher; Teo, Wei Wen; Cho, Soonweng; Zhang, Zhe; Visvanathan, Kala; Jeter, Stacie; Argani, Pedram; Wang, Chenguang; Lyman, Jaclyn P.; de Brot, Marina; Ingle, James N.; Boughey, Judy; McGuire, Kandace; King, Tari A.; Carey, Lisa A.; Cope, Leslie; Wolff, Antonio C.; Sukumar, Saraswati

    2015-01-01

    The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in a TCGA breast cancer methylome database. For cMethDNA, a fixed physiological level (50 copies) of artificially constructed, standard non-human reference DNA specific for each gene is introduced into in a constant volume of serum (300 μl) prior to purification of the DNA, facilitating a sensitive, specific, robust and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in Training (28 normal, 24 cancer) and Test (27 normal, 33 cancer) sets of recurrent Stage 4 patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy 2–11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. PMID:24737128

  19. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.

    PubMed

    Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Cordella, Angela; Campana, Antonella; Hashim, Adnan; Rizza, Pietro; Leggio, Antonella; Győrffy, Balázs; Simões, Bruno M; Clarke, Robert B; Weisz, Alessandro; Catalano, Stefania; Andò, Sebastiano

    2016-01-12

    Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression. PMID:26556856

  20. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

    PubMed Central

    Ibrahim, Safaa A.; Katara, Gajendra K.; Kulshrestha, Arpita; Jaiswal, Mukesh K.; Amin, Magdy A.; Beaman, Kenneth D.

    2015-01-01

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  1. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    PubMed

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer. PMID:25971583

  2. Decreased expression of ADAMTS-1 in human breast tumors stimulates migration and invasion

    PubMed Central

    2013-01-01

    Background ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs) is a member of the ADAMTS family of metalloproteases. Here, we investigated mRNA and protein levels of ADAMTS-1 in normal and neoplastic tissues using qPCR, immunohistochemistry and immunoblot analyses, and we addressed the role of ADAMTS-1 in regulating migration, invasion and invadopodia formation in breast tumor cell lines. Results In a series of primary breast tumors, we observed variable levels of ADAMTS-1 mRNA expression but lower levels of ADAMTS-1 protein expression in human breast cancers as compared to normal tissue, with a striking decrease observed in high-malignancy cases (triple-negative for estrogen, progesterone and Her-2). This result prompted us to analyze the effect of ADAMTS-1 knockdown in breast cancer cells in vitro. MDA-MB-231 cells with depleted ADAMTS-1 expression demonstrated increased migration, invasion and invadopodia formation. The regulatory mechanisms underlying the effects of ADAMTS-1 may be related to VEGF, a growth factor involved in migration and invasion. MDA-MB-231 cells with depleted ADAMTS-1 showed increased VEGF concentrations in conditioned medium capable of inducing human endothelial cells (HUVEC) tubulogenesis. Furthermore, expression of the VEGF receptor (VEGFR2) was increased in MDA-MB-231 cells as compared to MCF7 cells. To further determine the relationship between ADAMTS-1 and VEGF regulating breast cancer cells, MDA-MB-231 cells with reduced expression of ADAMTS-1 were pretreated with a function-blocking antibody against VEGF and then tested in migration and invasion assays; both were partially rescued to control levels. Conclusions ADAMTS-1 expression was decreased in human breast tumors, and ADAMTS-1 knockdown stimulated migration, invasion and invadopodia formation in breast cancer cells in vitro. Therefore, this series of experiments suggests that VEGF is involved in the effects mediated by ADAMTS-1 in breast cancer cells. PMID

  3. The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

    PubMed

    Brennan, D J; O'Connor, D P; Laursen, H; McGee, S F; McCarthy, S; Zagozdzon, R; Rexhepaj, E; Culhane, A C; Martin, F M; Duffy, M J; Landberg, G; Ryden, L; Hewitt, S M; Kuhar, M J; Bernards, R; Millikan, R C; Crown, J P; Jirström, K; Gallagher, W M

    2012-07-26

    Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. PMID:22139072

  4. Integrated Bioinformatics Approach Reveals Crosstalk Between Tumor Stroma and Peripheral Blood Mononuclear Cells in Breast Cancer.

    PubMed

    He, Lang; Wang, Dan; Wei, Na; Guo, Zheng

    2016-01-01

    Breast cancer is now the leading cause of cancer death in women worldwide. Cancer progression is driven not only by cancer cell intrinsic alterations and interactions with tumor microenvironment, but also by systemic effects. Integration of multiple profiling data may provide insights into the underlying molecular mechanisms of complex systemic processes. We performed a bioinformatic analysis of two public available microarray datasets for breast tumor stroma and peripheral blood mononuclear cells, featuring integrated transcriptomics data, protein-protein interactions (PPIs) and protein subcellular localization, to identify genes and biological pathways that contribute to dialogue between tumor stroma and the peripheral circulation. Genes of the integrin family as well as CXCR4 proved to be hub nodes of the crosstalk network and may play an important role in response to stroma-derived chemoattractants. This study pointed to potential for development of therapeutic strategies that target systemic signals travelling through the circulation and interdict tumor cell recruitment. PMID:27039717

  5. In-vivo imaging of breast cancer with ultrasound tomography: probing the tumor environment

    NASA Astrophysics Data System (ADS)

    Duric, Nebojsa; Littrup, Peter; West, Erik; Ranger, Bryan; Li, Cuiping; Schmidt, Steven

    2011-03-01

    We report on the use of ultrasound tomography (UST) to characterize breast cancer and study the local and distant tumor environments. We have imaged the tumor and its environment in 3 cases of breast cancer using a UST prototype and its associated image reconstruction algorithms. After generating images of reflection, sound speed and attenuation, the images were fused in combinations that allowed visualization and characterization of the interior of the tumor as well as the tissue immediate to the tumor and beyond. The reflection UST images demonstrated the presence of spiculation, and architectural distortion, indicators of both local tumor invasion and distant involvement with surrounding tissues. Furthermore, the sound speed images showed halos of elevated sound speed surrounding the tumors, indicating a local environment characterized by stiff tissues. The combination of sound speed and attenuation images revealed that the tumor interiors were the stiffest tissues in the region studied. These features and characteristics are commensurate with the known biomechanical properties of cancer and may be manifestations of the desmoplastic process that is associated with tumor invasion. We propose that UST imaging may prove to be a valuable tool for characterizing cancers and studying the tumor invasion process.

  6. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status

    PubMed Central

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors’ ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  7. Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer

    SciTech Connect

    Planas-Silva, Maricarmen D. . E-mail: mcplanas@psu.edu; Bruggeman, Richard D.; Grenko, Ronald T.; Stanley Smith, J.

    2006-03-03

    The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src-Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.

  8. Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models.

    PubMed

    LaMontagne, Kenneth R; Butler, Jeannene; Marshall, Deborah J; Tullai, Jennifer; Gechtman, Ze'ev; Hall, Chassidy; Meshaw, Alan; Farrell, Francis X

    2006-02-01

    We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin alpha) and the effect of recombinant epoetins (epoetin alpha, epoetin beta, and darbepoetin alpha) alone or in combination with anticancer therapy on tumor growth in two well-established preclinical models of breast carcinoma (MDA-MB-231 and MCF-7 cell lines). Expression and localization of EPOR under hypoxic and normoxic conditions in MDA-MB-231 and MCF-7 cells were evaluated by immunoblotting, flow cytometry, and immunohistochemistry. EPOR binding was evaluated using [125I]rHuEPO. Proliferation, migration, and signaling in MDA-MB-231 and MCF-7 cells following treatment with rHuEPO were evaluated. Tumor growth was assessed following administration of recombinant epoetins alone and in combination with paclitaxel (anticancer therapy) in orthotopically implanted MDA-MB-231 and MCF-7 breast carcinoma xenograft models in athymic mice. EPOR expression was detected in both tumor cell lines. EPOR localization was found to be exclusively cytosolic and no specific [125I]rHuEPO binding was observed. There was no stimulated migration, proliferation, or activation of mitogen-activated protein kinase and AKT following rHuEPO treatment. In mice, treatment with recombinant epoetins alone and in combination with paclitaxel resulted in equivalent tumor burdens compared with vehicle-treated controls. Results from our study suggest that although EPOR expression was observed in two well-established breast carcinoma cell lines, it was localized to a cytosolic distribution and did not transduce a signaling cascade in tumors that leads to tumor growth. The addition of recombinant epoetins to paclitaxel did not affect the outcome of paclitaxel therapy in breast carcinoma xenograft models. These results show that recombinant epoetins do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by numerous variables

  9. Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer.

    PubMed

    Forghani, Parvin; Khorramizadeh, Mohammad R; Waller, Edmund K

    2014-04-01

    Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b(+) Gr-1(+) MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b(+) Gr-1(+) MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs. PMID:24574320

  10. True Recurrence Versus New Primary: An Analysis of Ipsilateral Breast Tumor Recurrences After Breast-Conserving Therapy

    SciTech Connect

    Panet-Raymond, Valerie; Truong, Pauline T.; McDonald, Rachel E.; Alexander, Cheryl; Ross, Louetta; Ryhorchuk, Aleata; Watson, Peter H.

    2011-10-01

    Purpose: Ipsilateral breast tumor recurrence (IBTR) can occur in 5-20% of women with early-stage breast cancer treated with breast-conserving therapy. Two entities of IBTR have been described: true recurrence (TR), suggested to be regrowth of disease at the tumor bed, and new primary (NP), distinct from the index lesion in histology and location. This study compared survival outcomes between two patient cohorts classified clinically as having either TR or NP. Methods and Materials: Between 1989 and 1999, 6,020 women were referred to the BC Cancer Agency with newly diagnosed pT1-2, N0-1, M0 invasive breast cancer, treated with breast-conserving surgery. Of these, 289 patients had pathologically confirmed IBTR. Retrospective analysis was performed, and a set of decision rules was applied to classify cases as TR or NP based on change in histology, grade, hormone receptor status, and tumor location. Of 289 patients, 129 (45%) were classified as having TR and 139 (48%) as having NP; 21 (7%) were unclassified. Results: The distributions of age at diagnosis, age at recurrence, and histopathologic factors were similar in the TR and NP cohorts (all p > 0.05). The mean time to recurrence was shorter in TR patients than in NP patients (4.8 years vs. 6.3 years, p = 0.001). Treatment of the IBTR did not differ between the two groups. In the TR and NP cohorts, breast cancer-specific survival was 55.7% vs. 61.3% (p = 0.93), and overall survival was 43.7% vs. 54.8% (p = 0.53). Conclusions: Time to recurrence is significantly shorter in patients with IBTR classified as true recurrence compared to new primary. Non-statistically significant trends for less favorable survival were observed for patients with TR. Further investigation of the hypothesis that TR and NP tumors are distinct entities with different survival prognoses will require standardized pathology review and molecular analyses.

  11. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo

    PubMed Central

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J.

    2015-01-01

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis. PMID:26452220

  12. In vivo photoacoustic imaging of breast cancer tumor with HER2-targeted nanodiamonds

    NASA Astrophysics Data System (ADS)

    Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Jo, Janggun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

    2013-09-01

    Radiation-damaged nanodiamonds (NDs) are ideal optical contrast agents for photoacoustic (PA) imaging in biological tissues due to their good biocompatibility and high optical absorbance in the near-infrared (NIR) range. Acid treated NDs are oxidized to form carboxyl groups on the surface, functionalized with polyethylene glycol (PEG) and human epidermal growth factor receptor 2 (HER2) targeting ligand for breast cancer tumor imaging. Because of the specific binding of the ligand conjugated NDs to the HER2-overexpressing murine breast cancer cells (4T1.2 neu), the tumor tissues are significantly delineated from the surrounding normal tissue at wavelength of 820 nm under the PA imaging modality. Moreover, HER2 targeted NDs (HER2-PEG-NDs) result in higher accumulation in HER2 positive breast tumors as compared to non-targeted NDs after intravenous injection (i.v.). Longer retention time of HER-PEG-NDs is observed in HER2 overexpressing tumor model than that in negative tumor model (4T1.2). This demonstrates that targeting moiety conjugated NDs have great potential for the sensitive detection of cancer tumors and provide an attractive delivery strategy for anti-cancer drugs.

  13. Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

    PubMed

    Longo, João Paulo Figueiró; Muehlmann, Luis Alexandre; Miranda-Vilela, Ana Luisa; Portilho, Flávia Arruda; de Souza, Ludmilla Regina; Silva, Jaqueline Rodrigues; Lacava, Zulmira Guerrero Marques; Bocca, Anamelia Lorenzetti; Chaves, Sacha Braun; Azevedo, Ricardo Bentes

    2016-04-01

    The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts. PMID:27301195

  14. Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment

    PubMed Central

    Seoane, Samuel; Arias, Efigenia; Sigueiro, Rita; Sendon-Lago, Juan; Martinez-Ordoñez, Anxo; Castelao, Esteban; Eiró, Noemí; Garcia-Caballero, Tomás; Macia, Manuel; Lopez-Lopez, Rafael; Maestro, Miguel; Vizoso, Francisco; Mouriño, Antonio; Perez-Fernandez, Roman

    2015-01-01

    The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels. Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy. PMID:25992773

  15. Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum sanctum

    PubMed Central

    Nangia-Makker, Pratima; Tait, Larry; Hogan, Victor; Shekhar, Malathy P.V.; Funasaka, Tatsuyoshi; Raz, Avraham

    2013-01-01

    Ocimum sanctum (OS) is a traditionally used medicinal herb, which shows anti-oxidant, anti-carcinogenic, radio-protective and free radical scavenging properties. So far no detailed studies have been reported on its effects on human cancers. Thus, we analyzed its effects on human breast cancer utilizing in vitro and in vivo methodologies. Aqueous extracts were prepared from the mature leaves of Ocimum sanctum cultivated devoid of pesticides. Tumor progression and angiogenesis related processes like chemotaxis, proliferation, apoptosis, 3-dimensional growth and morphogenesis, angiogenesis, and tumor growth were studied in the presence or absence of the extract and in some experiments a comparison was made with purified commercially available eugenol, apigenin and ursolic acid. Aqueous OS leaf extract inhibits proliferation, migration, anchorage independent growth, three dimensional growth and morphogenesis, and induction of COX-2 protein in breast cancer cells. A comparative analysis with eugenol, apigenin and ursolic acid showed that the inhibitory effects on chemotaxis and three dimensional morphogenesis of breast cancer cells were specific to OS extract. In addition, OS extracts also reduced tumor size and neoangiogenesis in a MCF10 DCIS.com xenograft model of human DCIS. This is the first detailed report showing that OS leaf extract may be of value as a breast cancer preventive and therapeutic agent and might be considered as additional additive in the arsenal of components aiming at combating breast cancer progression and metastasis. PMID:17437270

  16. Metabolomics of human breast cancer: new approaches for tumor typing and biomarker discovery

    PubMed Central

    2012-01-01

    Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development. PMID:22546809

  17. Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion

    PubMed Central

    Roselli, Séverine; Pundavela, Jay; Demont, Yohann; Faulkner, Sam; Keene, Sheridan; Attia, John; Jiang, Chen Chen; Zhang, Xu Dong; Walker, Marjorie M.; Hondermarck, Hubert

    2015-01-01

    The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion. PMID:25871389

  18. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; Cuomo, Arturo; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression. PMID:26064880

  19. Viscoelastic Imaging of Breast Tumor Microenvironment With Ultrasound

    PubMed Central

    Insana, Michael F.; Pellot-Barakat, Claire; Sridhar, Mallika; Lindfors, Karen K.

    2009-01-01

    Imaging systems are most effective for detection and classification when they exploit contrast mechanisms specific to particular disease processes. A common example is mammography, where the contrast depends on local changes in cell density and the presence of microcalcifications. Unfortunately the specificity for classifying malignant breast disease is relatively low for many current diagnostic techniques. This paper describes a new ultrasonic technique for imaging the viscoelastic properties of breast tissue. The mechanical properties of glandular breast tissue, like most biopolymers, react to mechanical stimuli in a manner specific to the microenvironment of the tissue. Elastic properties allow noninvasive imaging of desmoplasia while viscous properties describe metabolism-dependent features such as pH. These ultrasonic methods are providing new tools for studying disease mechanisms as well as improving diagnosis. PMID:15838608

  20. Application of imaging mass spectrometry for the molecular diagnosis of human breast tumors

    PubMed Central

    Mao, Xinxin; He, Jiuming; Li, Tiegang; Lu, Zhaohui; Sun, Jian; Meng, Yunxiao; Abliz, Zeper; Chen, Jie

    2016-01-01

    Distinguishing breast invasive ductal carcinoma (IDC) and breast ductal carcinoma in situ (DCIS) is a key step in breast surgery, especially to determine whether DCIS is associated with tumor cell micro-invasion. However, there is currently no reliable method to obtain molecular information for breast tumor analysis during surgery. Here, we present a novel air flow-assisted ionization (AFAI) mass spectrometry imaging method that can be used in ambient environments to differentiate breast cancer by analyzing lipids. In this study, we demonstrate that various subtypes and histological grades of IDC and DCIS can be discriminated using AFAI-MSI: phospholipids were more abundant in IDC than in DCIS, whereas fatty acids were more abundant in DCIS than in IDC. The classification of specimens in the subtype and grade validation sets showed 100% and 78.6% agreement with the histopathological diagnosis, respectively. Our work shows the rapid classification of breast cancer utilizing AFAI-MSI. This work suggests that this method could be developed to provide surgeons with nearly real-time information to guide surgical resections. PMID:26868906

  1. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal

    PubMed Central

    Zhou, Bing; Damrauer, Jeffrey S.; Bailey, Sean T.; Hadzic, Tanja; Jeong, Youngtae; Clark, Kelly; Fan, Cheng; Murphy, Laura; Lee, Cleo Y.; Troester, Melissa A.; Miller, C. Ryan; Jin, Jian; Darr, David; Perou, Charles M.; Levine, Ross L.; Diehn, Maximilian; Kim, William Y.

    2014-01-01

    Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy. PMID:24435044

  2. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal.

    PubMed

    Zhou, Bing; Damrauer, Jeffrey S; Bailey, Sean T; Hadzic, Tanja; Jeong, Youngtae; Clark, Kelly; Fan, Cheng; Murphy, Laura; Lee, Cleo Y; Troester, Melissa A; Miller, C Ryan; Jin, Jian; Darr, David; Perou, Charles M; Levine, Ross L; Diehn, Maximilian; Kim, William Y

    2014-02-01

    Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy. PMID:24435044

  3. Application of imaging mass spectrometry for the molecular diagnosis of human breast tumors.

    PubMed

    Mao, Xinxin; He, Jiuming; Li, Tiegang; Lu, Zhaohui; Sun, Jian; Meng, Yunxiao; Abliz, Zeper; Chen, Jie

    2016-01-01

    Distinguishing breast invasive ductal carcinoma (IDC) and breast ductal carcinoma in situ (DCIS) is a key step in breast surgery, especially to determine whether DCIS is associated with tumor cell micro-invasion. However, there is currently no reliable method to obtain molecular information for breast tumor analysis during surgery. Here, we present a novel air flow-assisted ionization (AFAI) mass spectrometry imaging method that can be used in ambient environments to differentiate breast cancer by analyzing lipids. In this study, we demonstrate that various subtypes and histological grades of IDC and DCIS can be discriminated using AFAI-MSI: phospholipids were more abundant in IDC than in DCIS, whereas fatty acids were more abundant in DCIS than in IDC. The classification of specimens in the subtype and grade validation sets showed 100% and 78.6% agreement with the histopathological diagnosis, respectively. Our work shows the rapid classification of breast cancer utilizing AFAI-MSI. This work suggests that this method could be developed to provide surgeons with nearly real-time information to guide surgical resections. PMID:26868906

  4. Prognostic factors of phyllodes tumor of the breast.

    PubMed

    Roa, Juan Carlos; Tapia, Oscar; Carrasco, Paula; Contreras, Enrique; Araya, Juan Carlos; Muñoz, Sergio; Roa, Iván

    2006-06-01

    The phyllodes tumor is characterized by its tendency to recur locally and occasionally to metastasize. The purpose of the present paper was to assess the prognostic value of clinical-morphological characteristics in patients with phyllodes tumor. Forty-seven cases of phyllodes tumors was studied; the World Health Organization classification was used and follow up was obtained. A total of 51%, 28% and 21% of the tumors were classified as benign, borderline and malignant, respectively. The adherence (P = 0.01), size >10 cm (P = 0.001), high mitotic activity (P = 0.03), infiltrative tumor margin (P = 0.0002) and type of surgery in malignant tumors (P = 0.02) proved to be good predictors of relapse. The presence of pain (P = 0.03), postmenopausal status (P < 0.04), heavy cellular pleomorphism (P = 0.007), high mitotic activity (P = 0.002), tumoral grade (P = 0.006) and metastasis (P < 0.00001) were prognostic factors of poor survival. Tumoral grade and some clinical-morphological characteristics of patients with phyllodes tumors have a significant impact on the prediction of its biological behavior. PMID:16704494

  5. Desmoid tumors of the bilateral breasts in a patient without Gardner syndrome: a case report and review of literature.

    PubMed

    Brown, Charles S; Jeffrey, Brenda; Korentager, Richard; Hughes, Kenneth

    2012-08-01

    Desmoid tumors constitute 0.02% to 0.03% of all tumors. Consequently, few case reports exist for breast desmoids, even fewer identifying bilateral disease. We present a case report of a patient with bilateral breast desmoids and shoulder desmoid without evidence of FAP or Gardner syndrome. This case report explores the clinical, radiographic, pathologic, and treatment elements for desmoid tumors as well as a review of the literature. PMID:21629058

  6. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    PubMed Central

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. PMID:25599228

  7. Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

    PubMed Central

    Habibi, Mehran; Kmieciak, Maciej; Graham, Laura; Morales, Johanna K; Bear, Harry D; Manjili, Masoud H

    2008-01-01

    Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC. PMID:18425677

  8. Chitosan-Based Thermoreversible Hydrogel as an in Vitro Tumor Microenvironment for Testing Breast Cancer Therapies

    PubMed Central

    2015-01-01

    Breast cancer is a major health problem for women worldwide. Although in vitro culture of established breast cancer cell lines is the most widely used model for preclinical assessment, it poorly represents the behavior of breast cancers in vivo. Acceleration of the development of effective therapeutic strategies requires a cost-efficient in vitro model that can more accurately resemble the in vivo tumor microenvironment. Here, we report the use of a thermoreversible poly(ethylene glycol)-g-chitosan hydrogel (PCgel) as an in vitro breast cancer model. We hypothesized that PCgel could provide a tumor microenvironment that promotes cultured cancer cells to a more malignant phenotype with drug and immune resistance. Traditional tissue culture plates and Matrigel were applied as controls in our studies. In vitro cellular proliferation and morphology, the secretion of angiogenesis-related growth factors and cytokines, and drug and immune resistance were assessed. Our results show that PCgel cultures promoted tumor aggregate formation, increased secretion of various angiogenesis- and metastasis-related growth factors and cytokines, and increased tumor cell resistance to chemotherapeutic drugs and immunotherapeutic T cells. This PCgel platform may offer a valuable strategy to bridge the gap between standard in vitro and costly animal studies for a wide variety of experimental designs. PMID:24779767

  9. Chitosan-based thermoreversible hydrogel as an in vitro tumor microenvironment for testing breast cancer therapies.

    PubMed

    Tsao, Ching-Ting; Kievit, Forrest M; Wang, Kui; Erickson, Ariane E; Ellenbogen, Richard G; Zhang, Miqin

    2014-07-01

    Breast cancer is a major health problem for women worldwide. Although in vitro culture of established breast cancer cell lines is the most widely used model for preclinical assessment, it poorly represents the behavior of breast cancers in vivo. Acceleration of the development of effective therapeutic strategies requires a cost-efficient in vitro model that can more accurately resemble the in vivo tumor microenvironment. Here, we report the use of a thermoreversible poly(ethylene glycol)-g-chitosan hydrogel (PCgel) as an in vitro breast cancer model. We hypothesized that PCgel could provide a tumor microenvironment that promotes cultured cancer cells to a more malignant phenotype with drug and immune resistance. Traditional tissue culture plates and Matrigel were applied as controls in our studies. In vitro cellular proliferation and morphology, the secretion of angiogenesis-related growth factors and cytokines, and drug and immune resistance were assessed. Our results show that PCgel cultures promoted tumor aggregate formation, increased secretion of various angiogenesis- and metastasis-related growth factors and cytokines, and increased tumor cell resistance to chemotherapeutic drugs and immunotherapeutic T cells. This PCgel platform may offer a valuable strategy to bridge the gap between standard in vitro and costly animal studies for a wide variety of experimental designs. PMID:24779767

  10. Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-ribose) polymerase inhibition

    PubMed Central

    Yang, Eddy S.; Nowsheen, Somaira; Rahman, Mohammad A.; Cook, Rebecca S.; Xia, Fen

    2013-01-01

    Poly(ADP-ribose) polymerase inhibitors have gained recent attention due to their highly selective killing of BRCA1/2 mutated and DNA double strand break (DSB) repair deficient tumors. Unfortunately, the majority of sporadic breast cancers carry wild-type BRCA1/2 and are proficient in DSB repair. We and others have shown that BRCA1 is a nuclear/cytoplasm shuttling protein which is transiently exported from the nucleus to the cytosol upon various stimuli. Thus, we hypothesized that depletion of nuclear BRCA1 would compromise DSB repair and subsequently render sporadic tumors susceptible to PARP inhibition. Indeed, in human sporadic breast cancer cells with functional BRCA1 and proficient DSB repair, a transient nuclear depletion of BRCA1 and subsequent HR repair deficit was induced with either truncated BRCA1 or irradiation. This rendered these human sporadic breast cancer cells susceptible to PARP inhibition. These observations were confirmed genetically using mislocated BRCA1 mutants as well as in vivo in mice bearing breast tumor xenografts. These data support the potential strategy of targeting BRCA1 location to convert BRCA1-proficient sporadic tumors to be susceptible to the synthetic lethal combination with PARP inhibitors. PMID:22962264

  11. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

    PubMed Central

    Saal, Lao H; Gruvberger-Saal, Sofia K; Persson, Camilla; Lövgren, Kristina; Jumppanen, Mervi; Staaf, Johan; Jönsson, Göran; Pires, Maira M; Maurer, Matthew; Holm, Karolina; Koujak, Susan; Subramaniyam, Shivakumar; Vallon-Christersson, Johan; Olsson, Haökan; Su, Tao; Memeo, Lorenzo; Ludwig, Thomas; Ethier, Stephen P; Krogh, Morten; Szabolcs, Matthias; Murty, Vundavalli VVS; Isola, Jorma; Hibshoosh, Hanina; Parsons, Ramon; Borg, Åke

    2010-01-01

    Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1–3. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype3–5; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair. PMID:18066063

  12. Breast tumor bank: an important resource for developing translational cancer research in Romania.

    PubMed

    Braicu, Cornelia; Berindan-Neagoe, Ioana; Pileczki, Valentina; Cojocneanu-Petric, Roxana; Pop, Laura-Ancuţa; Puscas, Emil; Irimie, Alexandru; Buiga, Rares

    2014-01-01

    The development of a breast tumor bank facilitates translational research. Easy access to biological specimens allows scientists to translate the outcomes of basic science into clinically useful knowledge. The breast tumor bank is particularly useful for triple negative breast cancer (TNBC) that is sporadic but exhibits the worst prognosis. It serves as a national resource that includes biological samples of paraffin-embedded and frozen tumor tissue with corresponding pathological and clinical data. During the first two years, the bank has accrued data and samples from more than 254 breast cancer cases. Based on this information, we observed a higher number of samples with ER (estrogen receptor) and PR (progesterone receptor) positive and negative for Her2. Also, 30% of the total number of cases was defined as TNBC. The use of tumor banks in research and diagnosis allows for the design of different studies that can bring reliable results that may improve the lives of patients, especially those diagnosed with TNBC. PMID:24878812

  13. Non-invasive thermal IR detection of breast tumor development in vivo

    NASA Astrophysics Data System (ADS)

    Case, Jason R.; Young, Madison A.; Dréau, D.; Trammell, Susan R.

    2015-03-01

    Lumpectomy coupled with radiation therapy and/or chemotherapy comprises the treatment of breast cancer for many patients. We are developing an enhanced thermal IR imaging technique that can be used in real-time to guide tissue excision during a lumpectomy. This novel enhanced thermal imaging method is a combination of IR imaging (8- 10 μm) and selective heating of blood (~0.5 °C) relative to surrounding water-rich tissue using LED sources at low powers. Post-acquisition processing of these images highlights temporal changes in temperature and is sensitive to the presence of vascular structures. In this study, fluorescent and enhanced thermal imaging modalities were used to estimate breast cancer tumor volumes as a function of time in 19 murine subjects over a 30-day study period. Tumor volumes calculated from fluorescent imaging follow an exponential growth curve for the first 22 days of the study. Cell necrosis affected the tumor volume estimates based on the fluorescent images after Day 22. The tumor volumes estimated from enhanced thermal imaging show exponential growth over the entire study period. A strong correlation was found between tumor volumes estimated using fluorescent imaging and the enhanced IR images, indicating that enhanced thermal imaging is capable monitoring tumor growth. Further, the enhanced IR images reveal a corona of bright emission along the edges of the tumor masses. This novel IR technique could be used to estimate tumor margins in real-time during surgical procedures.

  14. Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

    PubMed

    Zhang, Y-W; Nasto, R E; Varghese, R; Jablonski, S A; Serebriiskii, I G; Surana, R; Calvert, V S; Bebu, I; Murray, J; Jin, L; Johnson, M; Riggins, R; Ressom, H; Petricoin, E; Clarke, R; Golemis, E A; Weiner, L M

    2016-03-31

    Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers. PMID:26165839

  15. Localized Hypoxia Results in Spatially Heterogeneous Metabolic Signatures in Breast Tumor Models1

    PubMed Central

    Jiang, Lu; Greenwood, Tiffany R; Artemov, Dmitri; Raman, Venu; Winnard, Paul T; Heeren, Ron MA; Bhujwalla, Zaver M; Glunde, Kristine

    2012-01-01

    Tumor hypoxia triggers signaling cascades that significantly affect biologic outcomes such as resistance to radiotherapy and chemotherapy in breast cancer. Hypoxic regions in solid tumor are spatially heterogeneous. Therefore, delineating the origin and extent of hypoxia in tumors is critical. In this study, we have investigated the effect of hypoxia on different metabolic pathways, such as lipid and choline metabolism, in a human breast cancer model. Human MDA-MB-231 breast cancer cells and tumors, which were genetically engineered to express red fluorescent tdTomato protein under hypoxic conditions, were used to investigate hypoxia. Our data were obtained with a novel three-dimensional multimodal molecular imaging platform that combines magnetic resonance (MR) imaging, MR spectroscopic imaging (MRSI), and optical imaging of hypoxia and necrosis. A higher concentration of noninvasively detected total choline-containing metabolites (tCho) and lipid CH3 localized in the tdTomato-fluorescing hypoxic regions indicated that hypoxia can upregulate tCho and lipid CH3 levels in this breast tumor model. The increase in tCho under hypoxia was primarily due to elevated phosphocholine levels as shown by in vitro MR spectroscopy. Elevated lipid CH3 levels detected under hypoxia were caused by an increase in mobile MR-detectable lipid droplets, as demonstrated by Nile Red staining. Our findings demonstrate that noninvasive MRSI can help delineate hypoxic regions in solid tumors by means of detecting the metabolic outcome of tumor hypoxia, which is characterized by elevated tCho and lipid CH3. PMID:22952426

  16. Bimodal Multiparameter-Based Approach for Benign-Malignant Classification of Breast Tumors.

    PubMed

    Ara, Sharmin R; Alam, Farzana; Rahman, Md Hadiur; Akhter, Shabnam; Awwal, Rayhana; Hasan, Kamrul

    2015-07-01

    Proposed here is a breast tumor classification technique using conventional ultrasound B-mode imaging and a new elasticity imaging-based bimodal multiparameter index. A set of conventional ultrasound (US) and ultrasound elastography (UE) parameters are studied, and among those, the effective ones whose independent as well as combined performance is found satisfactory are selected. To improve the combined US performance, two new US parameters are proposed: edge diffusivity, which assesses edge blurriness to differentiate malignant from benign lesions, and the shape asymmetry factor, which quantifies tumor shape irregularity by comparing the tumor boundary with an ellipse fitted to the lesion. Then a new bimodal multiparameter characterization index is defined to discriminate 201 pathologically confirmed breast tumors of which 56 are malignant lesions, 79 are fibroadenomas, 42 are cysts and 24 are inflammatory lesions. The weights of the multiparameter bimodal index are optimally computed using a genetic algorithm (GA). To evaluate the performance variation of the index on different data sets, the tumors are categorized into three classes: malignant lesion versus fibroadenoma, malignant lesion versus fibroadenoma and cyst and malignant lesion versus fibroadenoma, cyst and inflammation. The test results reveal that the proposed bimodal index achieves satisfactory quality metrics (e.g., 94.64%-98.21% sensitivity, 97.24%-100.00% specificity and 96.52%-99.44% accuracy) for classification of the aforementioned three classes of breast tumors. Its performance is also observed to be better in totality of the quality metrics sensitivity, specificity, accuracy, positive predictive value and negative predictive value as compared with that of a conventional bimodal index as well as unimodal multiparameter indices based on US or UE. It is suggested that the proposed simple bimodal linear classifier may assist radiologists in better diagnosis of breast tumors and help reduce the

  17. Monte Carlo design of optimal wire mesh collimator for breast tumor imaging process

    NASA Astrophysics Data System (ADS)

    Saad, W. H. M.; Roslan, R. E.; Mahdi, M. A.; Choong, W.-S.; Saion, E.; Saripan, M. I.

    2011-08-01

    This paper presents the modeling of breast tumor imaging process using wire mesh collimator gamma camera. Previous studies showed that the wire mesh collimator has a potential to improve the sensitivity of the tumor detection. In this paper, we extend our research significantly, to find an optimal configuration of the wire mesh collimator specifically for semi-compressed breast tumor detection, by looking into four major factors: weight, sensitivity, spatial resolution and tumor contrast. The numbers of layers in the wire mesh collimator is varied to optimize the collimator design. The statistical variations of the results are studied by simulating multiple realizations for each experiment using different starting random numbers. All the simulation environments are modeled using Monte Carlo N-Particle Code (MCNP). The quality of the detection is measured directly by comparing the sensitivity, spatial resolution and tumor contrast of the images produced by the wire mesh collimator and benchmarked that with a standard multihole collimator. The proposed optimal configuration of the wire mesh collimator is optimized by selecting the number of layers in wire mesh collimator, where the tumor contrast shows a relatively comparable value to the multihole collimator, when it is tested with uniformly semi-compressed breast phantom. The wire mesh collimator showed higher number of sensitivity because of its loose arrangement while the spatial resolution of wire mesh collimator does not shows much different compared to the multihole collimator. With a relatively good tumor contrast and spatial resolution, and increased in sensitivity, a new proposed wire mesh collimator gives a significant improvement in the wire mesh collimator design for breast cancer imaging process. The proposed collimator configuration is reduced to 44.09% from the total multihole collimator weight.

  18. Host genotype and tumor phenotype of chemokine decoy receptors integrally affect breast cancer relapse

    PubMed Central

    Shao, Zhi-Ming

    2015-01-01

    Purpose Chemokines may play vital roles in breast cancer progression and metastasis. The primary members of chemokine decoy receptors (CDR), DARC and D6, are expressed in breast tumors and lymphatic/hematogenous vessels. CDRs sequestrate the pro-malignant chemokines. We hypothesized that breast cancer patients carrying different levels of CDR expression in tumor and/or in host might have differing clinical outcomes. Methods This prospective observational study measured both expression and germline genotype of DARC and D6 in 463 primary breast cancer patients enrolled between 2004 and 2006. The endpoint was breast cancer relapse-free survival (RFS). Results There was a significant association between the co-expression of CDR (immunohistochemical expression of both DARC and D6) with RFS (hazard ratio [HR] of 0.32, 95% confidence interval [CI] 0.19 to 0.54). Furthermore, the co-genotype of two non-synonymous polymorphisms (with two major alleles of DARC-rs12075 and D6-rs2228468 versus the others) significantly related to relapse. Mechanistically, the variant-alleles of these two polymorphisms significantly decreased by 20–30% of CCL2/CCL5 (CDR ligands) levels relative to their major counterparts. Multivariate analysis highlighted that the co-expression and co-genotype of CDR were independent predictors of RFS, with HR of 0.46 (95% CI 0.27 to 0.80) and 0.56 (95% CI 0.37 to 0.85), respectively. The addition of host CDR genetic information to tumor-based factors (including co-expression of CDR) improved the relapse prediction ability (P = 0.02 of AUC comparison). Conclusion The host genotype and tumor phenotype of CDR integrally affect breast cancer relapse. Host-related factors should be considered for individualized prediction of prognosis. PMID:26314842

  19. Fourier-based shape feature extraction technique for computer-aided B-Mode ultrasound diagnosis of breast tumor.

    PubMed

    Lee, Jong-Ha; Seong, Yeong Kyeong; Chang, Chu-Ho; Park, Jinman; Park, Moonho; Woo, Kyoung-Gu; Ko, Eun Young

    2012-01-01

    Early detection of breast tumor is critical in determining the best possible treatment approach. Due to its superiority compared with mammography in its possibility to detect lesions in dense breast tissue, ultrasound imaging has become an important modality in breast tumor detection and classification. This paper discusses the novel Fourier-based shape feature extraction techniques that provide enhanced classification accuracy for breast tumor in the computer-aided B-mode ultrasound diagnosis system. To demonstrate the effectiveness of the proposed method, experiments were performed using 4,107 ultrasound images with 2,508 malignancy cases. Experimental results show that the breast tumor classification accuracy of the proposed technique was 15.8%, 5.43%, 17.32%, and 13.86% higher than the previous shape features such as number of protuberances, number of depressions, lobulation index, and dissimilarity, respectively. PMID:23367430

  20. Quantification of tumor changes during neoadjuvant chemotherapy with longitudinal breast DCE-MRI registration

    NASA Astrophysics Data System (ADS)

    Wu, Jia; Ou, Yangming; Weinstein, Susan P.; Conant, Emily F.; Yu, Ning; Hoshmand, Vahid; Keller, Brad; Ashraf, Ahmed B.; Rosen, Mark; DeMichele, Angela; Davatzikos, Christos; Kontos, Despina

    2015-03-01

    Imaging plays a central role in the evaluation of breast tumor response to neoadjuvant chemotherapy. Image-based assessment of tumor change via deformable registration is a powerful, quantitative method potentially to explore novel information of tumor heterogeneity, structure, function, and treatment response. In this study, we continued a previous pilot study to further validate the feasibility of an open source deformable registration algorithm DRAMMS developed within our group as a means to analyze spatio-temporal tumor changes for a set of 14 patients with DCE-MR imaging. Two experienced breast imaging radiologists marked landmarks according to their anatomical meaning on image sets acquired before and during chemotherapy. Yet, chemotherapy remarkably changed the anatomical structure of both tumor and normal breast tissue, leading to significant discrepancies between both raters for landmarks in certain areas. Therefore, we proposed a novel method to grade the manually denoted landmarks into different challenge levels based on the inter-rater agreement, where a high level indicates significant discrepancies and considerable amounts of anatomical structure changes, which would indeed impose giant problem for the following registration algorithm. It is interesting to observe that DRAMMS performed in a similar manner as the human raters: landmark errors increased as inter-rater differences rose. Among all selected six deformable registration algorithms, DRAMMS achieves the highest overall accuracy, which is around 5.5 mm, while the average difference between human raters is 3 mm. Moreover, DRAMMS performed consistently well within both tumor and normal tissue regions. Lastly, we comprehensively tuned the fundamental parameters of DRAMMS to better understand DRAMMS to guide similar works in the future. Overall, we further validated that DRAMMS is a powerful registration tool to accurately quantify tumor changes and potentially predict early tumor response to

  1. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

    PubMed Central

    2013-01-01

    Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage

  2. Complex permittivities of breast tumor tissues obtained from cancer surgeries

    NASA Astrophysics Data System (ADS)

    Sugitani, Takumi; Kubota, Shin-ichi; Kuroki, Shin-ichiro; Sogo, Kenta; Arihiro, Koji; Okada, Morihito; Kadoya, Takayuki; Hide, Michihiro; Oda, Miyo; Kikkawa, Takamaro

    2014-06-01

    The variability in measurements of complex permittivities of tumor tissues between multiple samples could be attributed to the volume fraction of cancer cells in the excised tumor tissue. By the use of a digital photomicrograph image and hematoxylin-eosin staining, it was found that the malignant tumor tissue was not fully occupied by the cancer cells, but the cells were distributed locally in the stroma cells depending on the growth of cancer. The results showed that the volume fraction of cancer cells in the tumor tissue had a correlation to the measured conductivity and dielectric constant in the frequency range from 1 GHz to 6 GHz. It introduces a method to understand and gauge variability in measurements between different tumors.

  3. Proteomic profiling of 13 paired ductal infiltrating breast carcinomas and non-tumoral adjacent counterparts.

    PubMed

    Pucci-Minafra, Ida; Cancemi, Patrizia; Marabeti, Maria Rita; Albanese, Nadia Ninfa; Di Cara, Gianluca; Taormina, Pietra; Marrazzo, Antonio

    2007-01-01

    According to recent statistics, breast cancer remains one of the leading causes of death among women in Western countries. Breast cancer is a complex and heterogeneous disease, presently classified into several subtypes according to their cellular origin. Among breast cancer histotypes, infiltrating ductal carcinoma represents the most common and potentially aggressive form. Despite the current progress achieved in early cancer detection and treatment, including the new generation of molecular therapies, there is still need for identification of multiparametric biomarkers capable of discriminating between cancer subtypes and predicting cancer progression for personalized therapies. One established step in this direction is the proteomic strategy, expected to provide enough information on breast cancer profiling. To this aim, in the present study we analyzed 13 breast cancer tissues and their matched non-tumoral tissues by 2-DE. Collectively, we identified 51 protein spots, corresponding to 34 differentially expressed proteins, which may represent promising candidate biomarkers for molecular-based diagnosis of breast cancer and for pattern discovery. The relevance of these proteins as factors contributing to breast carcinogenesis is discussed. PMID:21136615

  4. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer

    PubMed Central

    Caceres, Sara; Peña, Laura; Silvan, Gema; Illera, Maria J.; Woodward, Wendy A.; Reuben, James M.; Illera, Juan C.

    2016-01-01

    Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6–8-week-old male and female mice were inoculated subcutaneously with a suspension of 106IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors. PMID:27195300

  5. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer.

    PubMed

    Caceres, Sara; Peña, Laura; Silvan, Gema; Illera, Maria J; Woodward, Wendy A; Reuben, James M; Illera, Juan C

    2016-01-01

    Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6-8-week-old male and female mice were inoculated subcutaneously with a suspension of 10(6)IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors. PMID:27195300

  6. Study of thermal effect on breast tumor metabolism and growth using metabonomics.

    PubMed

    Dai, Guangchen; Jia, Wei; Hu, Xiaofang; Xu, Lisa X

    2013-01-01

    In this study, the biological effects of long-term mild hyperthermia treatment on tumor metabolism and growth were investigated using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. Periodic thermal treatment (12 hours per day) was applied to tumors and carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The metabolites of tumor tissues were analyzed by gas chromatography-mass spectrometry. The results showed that the growth rate of thermally treated tumors was inversely related to the abundance of long chain fatty acids and acyl glycerols identified in tumor tissues. In the first two weeks, the growth of thermally treated tumors was significantly inhibited, while there was an obvious accumulation of long chain fatty acids and acyl glycerols in tumor tissues. In the third week, the thermally treated tumors adapted to the thermal environment and started to regrow, while the abundance of long chain fatty acids and acyl glycerols decreased in the tumor tissues. These observations suggested that the blockade of long chain fatty acid synthesis during mild hyperthermia treatment of tumors could improve the long-term treatment effect by limiting the supply of substance and energy for tumor re-growth. PMID:24110083

  7. A novel thermal treatment modality for controlling breast tumor growth and progression.

    PubMed

    Xie, Yifan; Liu, Ping; Xu, Lisa X

    2012-01-01

    The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future. PMID:23367225

  8. Towards intraoperative assessment of tumor margins in breast surgery using optical coherence elastography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Kennedy, Brendan F.; Wijesinghe, Philip; Allen, Wes M.; Chin, Lixin; Latham, Bruce; Saunders, Christobel M.; Sampson, David D.

    2016-03-01

    Surgical excision of tumor is a critical factor in the management of breast cancer. The most common surgical procedure is breast-conserving surgery. The surgeon's goal is to remove the tumor and a rim of healthy tissue surrounding the tumor: the surgical margin. A major issue in breast-conserving surgery is the absence of a reliable tool to guide the surgeon in intraoperatively assessing the margin. A number of techniques have been proposed; however, the re-excision rate remains high and has been reported to be in the range 30-60%. New tools are needed to address this issue. Optical coherence elastography (OCE) shows promise as a tool for intraoperative tumor margin assessment in breast-conserving surgery. Further advances towards clinical translation are limited by long scan times and small fields of view. In particular, scanning over sufficient areas to assess the entire margin in an intraoperative timeframe has not been shown to be feasible. Here, we present a protocol allowing ~75% of the surgical margins to be assessed within 30 minutes. To achieve this, we have incorporated a 65 mm-diameter (internal), wide-aperture annular piezoelectric transducer, allowing the entire surface of the excised tumor mass to be automatically imaged in an OCT mosaic comprised of 10 × 10 mm tiles. As OCT is effective in identifying adipose tissue, our protocol uses the wide-field OCT to selectively guide subsequent local OCE scanning to regions of solid tissue which often present low contrast in OCT images. We present promising examples from freshly excised human breast tissue.

  9. “Ruptured” malignant phyllodes tumor of the breast: a case report

    PubMed Central

    Ditsatham, Chagkrit; Somwangprasert, Areewan; Watcharachan, Kirati; Wongmaneerung, Phanchaporn

    2016-01-01

    Phyllodes tumor or cystosarcoma phyllodes is a rare disease and is usually seen in middle-aged patients. Ruptured phyllodes tumor is a very rare condition. Our study reports patient presentation, diagnosis method, and treatment of an unusual case. A 58-year-old premenopausal female was diagnosed with a phyllodes tumor and presented with a rapidly growing mass for 2 months that ruptured 1 month later. She underwent simple mastectomy at the left side of her breast and received adjuvant radiotherapy. No recurrence was found 4 months after operation. PMID:26952179

  10. PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model.

    PubMed

    Du, J; Yang, M; Chen, S; Li, D; Chang, Z; Dong, Z

    2016-06-23

    Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor. PMID:26455327

  11. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model.

    PubMed

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-12-14

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([(64)Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [(64)Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy. PMID:26376843

  12. MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.

    PubMed

    Deng, Lu; Shang, Li; Bai, Shoumin; Chen, Ji; He, Xueyan; Martin-Trevino, Rachel; Chen, Shanshan; Li, Xiao-Yan; Meng, Xiaojie; Yu, Bin; Wang, Xiaolin; Liu, Yajing; McDermott, Sean P; Ariazi, Alexa E; Ginestier, Christophe; Ibarra, Ingrid; Ke, Jia; Luther, Tahra; Clouthier, Shawn G; Xu, Liang; Shan, Ge; Song, Erwei; Yao, Herui; Hannon, Gregory J; Weiss, Stephen J; Wicha, Max S; Liu, Suling

    2014-11-15

    miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem-like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation. PMID:25217527

  13. MicroRNA100 Inhibits Self-Renewal of Breast Cancer Stem–like Cells and Breast Tumor Development

    PubMed Central

    Deng, Lu; Shang, Li; Bai, Shoumin; Chen, Ji; He, Xueyan; Martin-Trevino, Rachel; Chen, Shanshan; Li, Xiao-yan; Meng, Xiaojie; Yu, Bin; Wang, Xiaolin; Liu, Yajing; McDermott, Sean P.; Ariazi, Alexa E.; Ginestier, Christophe; Ibarra, Ingrid; Ke, Jia; Luther, Tahra; Clouthier, Shawn G.; Xu, Liang; Shan, Ge; Song, Erwei; Yao, Herui; Hannon, Gregory J.; Weiss, Stephen J.; Wicha, Max S.; Liu, Suling

    2015-01-01

    miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem-like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation. PMID:25217527

  14. Ultrasound Shear Wave Simulation of Breast Tumor Using Nonlinear Tissue Elasticity.

    PubMed

    Park, Dae Woo

    2015-01-01

    Shear wave elasticity imaging (SWEI) can assess the elasticity of tissues, but the shear modulus estimated in SWEI is often less sensitive to a subtle change of the stiffness that produces only small mechanical contrast to the background tissues. Because most soft tissues exhibit mechanical nonlinearity that differs in tissue types, mechanical contrast can be enhanced if the tissues are compressed. In this study, a finite element- (FE-) based simulation was performed for a breast tissue model, which consists of a circular (D: 10 mm, hard) tumor and surrounding tissue (soft). The SWEI was performed with 0% to 30% compression of the breast tissue model. The shear modulus of the tumor exhibited noticeably high nonlinearity compared to soft background tissue above 10% overall applied compression. As a result, the elastic modulus contrast of the tumor to the surrounding tissue was increased from 0.46 at 0% compression to 1.45 at 30% compression. PMID:27293476

  15. The hypoxic tumor microenvironment: A driving force for breast cancer progression.

    PubMed

    Semenza, Gregg L

    2016-03-01

    Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. PMID:26079100

  16. Ultrasound Shear Wave Simulation of Breast Tumor Using Nonlinear Tissue Elasticity

    PubMed Central

    Park, Dae Woo

    2016-01-01

    Shear wave elasticity imaging (SWEI) can assess the elasticity of tissues, but the shear modulus estimated in SWEI is often less sensitive to a subtle change of the stiffness that produces only small mechanical contrast to the background tissues. Because most soft tissues exhibit mechanical nonlinearity that differs in tissue types, mechanical contrast can be enhanced if the tissues are compressed. In this study, a finite element- (FE-) based simulation was performed for a breast tissue model, which consists of a circular (D: 10 mm, hard) tumor and surrounding tissue (soft). The SWEI was performed with 0% to 30% compression of the breast tissue model. The shear modulus of the tumor exhibited noticeably high nonlinearity compared to soft background tissue above 10% overall applied compression. As a result, the elastic modulus contrast of the tumor to the surrounding tissue was increased from 0.46 at 0% compression to 1.45 at 30% compression. PMID:27293476

  17. Optical imaging of breast tumor through temporal log-slope difference mappings.

    PubMed

    Guo, Zhixiong; Kan Wan, Siew; August, David A; Ying, Jinpin; Dunn, Stanley M; Semmlow, John L

    2006-02-01

    A novel optical temporal log-slope difference mapping approach is proposed for cancerous breast tumor detection. In this method, target tissues are illuminated by near-infrared (700-1000 nm) ultrashort laser pulses from various surface source points, and backscattered time-resolved light signals are collected at the same surface points. By analyzing the log-slopes of decaying signals over all points on the source-detection grid, a log-slope distribution on the surface is obtained. After administration of absorption contrast agents, the presence of cancerous tumors increases the decaying steepness of the transient signals. The mapping of log-slope difference between native tissue and absorption-enhanced cancerous tissue indicates the location and projection of tumors on the detection surface. In this paper, we examine this method in the detection of breast tumors in two model tissue phantoms through computer simulation. The first model has a spherical tumor of 6mm in diameter embedded at the tissue center. The second model is a large tissue phantom embedded with a non-centered spherical tumor 8mm in diameter. Monte Carlo methods were employed to simulate the light transport and signal measurement. It is shown that the tumor in both the tissue models will be accurately projected on the detection surface by the proposed log-slope difference mapping method. The image processing is very fast and does not require any inverse optimization in image reconstruction. PMID:16389079

  18. Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors

    SciTech Connect

    Singh, Preeti; Godbole, Madan; Rao, Geeta; Annarao, Sanjay; Mitra, Kalyan; Roy, Raja; Ingle, Arvind; Agarwal, Gaurav; Tiwari, Swasti

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer Molecular iodine (I{sub 2}) causes non-apoptotic cell death in MDA-MB231 breast tumor cells. Black-Right-Pointing-Pointer Autophagy is activated as a survival mechanism in response to I{sub 2} in MDA-MB231. Black-Right-Pointing-Pointer Autophagy inhibition sensitizes tumor cells to I{sub 2}-induced apoptotic cell death. Black-Right-Pointing-Pointer Autophagy inhibitor potentiates apoptosis and tumor regressive effects of I{sub 2} in mice. -- Abstract: Estrogen receptor negative (ER{sup -ve}) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I{sub 2}) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER{sup -ve}-p53 mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I{sub 2} (3 {mu}M) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER{sup -ve} mammary tumors could be sensitized to I{sub 2}-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I{sub 2} treated MDA-MB231 cells. Further, CQ (20 {mu}M) in combination with I{sub 2}, showed apoptotic features such as increased sub-G1 fraction ({approx}5-fold), expression of cleaved caspase-9 and -3 compared to I{sub 2} treatment alone. Flowcytometry of I{sub 2} and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p < 0.01) and translocation of cathepsin D activity to cytosol relative to I{sub 2} treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I{sub 2} and CQ co-treated mice relative to I{sub 2} or

  19. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    PubMed Central

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  20. Identification of Intrinsic Imaging Phenotypes for Breast Cancer Tumors: Preliminary Associations with Gene Expression Profiles1

    PubMed Central

    Ashraf, Ahmed Bilal; Daye, Dania; Gavenonis, Sara; Mies, Carolyn; Feldman, Michael; Rosen, Mark; Kontos, Despina

    2015-01-01

    Purpose To present a method for identifying intrinsic imaging phenotypes in breast cancer tumors and to investigate their association with prognostic gene expression profiles. Materials and Methods The authors retrospectively analyzed dynamic contrast material–enhanced (DCE) magnetic resonance (MR) images of the breast in 56 women (mean age, 55.6 years; age range, 37–74 years) diagnosed with estrogen receptor–positive breast cancer between 2005 and 2010. The study was approved by the institutional review board and compliant with HIPAA. The requirement to obtain informed consent was waived. Primary tumors were assayed with a validated gene expression assay that provides a score for the likelihood of recurrence. A multiparametric imaging phenotype vector was extracted for each tumor by using quantitative morphologic, kinetic, and spatial heterogeneity features. Multivariate linear regression was performed to test associations between DCE MR imaging features and recurrence likelihood. To identify intrinsic imaging phenotypes, hierarchical clustering was performed on the extracted feature vectors. Multivariate logistic regression was used to classify tumors at high versus low or medium risk of recurrence. To determine the additional value of intrinsic phenotypes, the phenotype category was tested as an additional variable. Receiver operating characteristic analysis and the area under the receiver operating characteristic curve (Az) were used to assess classification performance. Results There was a moderate correlation (r = 0.71, R2 = 0.50, P < .001) between DCE MR imaging features and the recurrence score. DCE MR imaging features were predictive of recurrence risk as determined by the surrogate assay, with an Az of 0.77 (P < .01). Four dominant imaging phenotypes were detected, with two including only low- and medium-risk tumors. When the phenotype category was used as an additional variable, the Az increased to 0.82 (P < .01). Conclusion Intrinsic imaging

  1. Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer

    PubMed Central

    Jardim-Perassi, Bruna Victorasso; Arbab, Ali S.; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R. S.; Iskander, A. S. M.; Shankar, Adarsh; Ali, Meser M.; de Campos Zuccari, Debora Aparecida Pires

    2014-01-01

    As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell

  2. Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays.

    PubMed

    Yang, Xiaohong R; Killian, J Keith; Hammond, Sue; Burke, Laura S; Bennett, Hunter; Wang, Yonghong; Davis, Sean R; Strong, Louise C; Neglia, Joseph; Stovall, Marilyn; Weathers, Rita E; Robison, Leslie L; Bhatia, Smita; Mabuchi, Kiyohiko; Inskip, Peter D; Meltzer, Paul

    2015-01-01

    Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an "amplifier" genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings. PMID:25764003

  3. ABCG2 is a potential marker of tumor-initiating cells in breast cancer.

    PubMed

    Sicchieri, Renata Danielle; da Silveira, Willian Abraham; Mandarano, Larissa Raquel Mouro; de Oliveira, Tatiane Mendes Gonçalves; Carrara, Hélio Humberto Angotti; Muglia, Valdair Francisco; de Andrade, Jurandyr Moreira; Tiezzi, Daniel Guimarães

    2015-12-01

    The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2

  4. A giant phyllodes tumor causing ulceration and severe breast disfigurement: case report and review of giant phyllodes

    PubMed Central

    Sbeih, Mohammed A.; Engdahl, Ryan; Landa, Marina; Ojutiku, Oreoluwa; Morrison, Norman; Depaz, Hector

    2015-01-01

    Phyllodes tumors are rare fibroepithelial tumors that account for <1% of the breast tumors in women. These tumors are often benign unilateral lesions of the female breast (70%). Less common are malignant phyllodes, which have the potential for hematogenous spread. Phyllodes tumors can be seen in all age groups, and the median age of presentation is 45 years. Surgery is the main form of treatment. Wide excisions with margins of 1cm are suggested. While smaller and moderate size phyllodes may typically be seen, gigantic ones are very rare. These may be seen in neglected tumors. By definition, a giant phyllodes tumor is one larger than 10 cm in diameter. We report a gigantic phyllodes tumor that grew over 7 years period causing significant ulceration and disfigurement and review features of these tumors and management. PMID:26703928

  5. A giant phyllodes tumor causing ulceration and severe breast disfigurement: case report and review of giant phyllodes.

    PubMed

    Sbeih, Mohammed A; Engdahl, Ryan; Landa, Marina; Ojutiku, Oreoluwa; Morrison, Norman; Depaz, Hector

    2015-01-01

    Phyllodes tumors are rare fibroepithelial tumors that account for <1% of the breast tumors in women. These tumors are often benign unilateral lesions of the female breast (70%). Less common are malignant phyllodes, which have the potential for hematogenous spread. Phyllodes tumors can be seen in all age groups, and the median age of presentation is 45 years. Surgery is the main form of treatment. Wide excisions with margins of 1cm are suggested. While smaller and moderate size phyllodes may typically be seen, gigantic ones are very rare. These may be seen in neglected tumors. By definition, a giant phyllodes tumor is one larger than 10 cm in diameter. We report a gigantic phyllodes tumor that grew over 7 years period causing significant ulceration and disfigurement and review features of these tumors and management. PMID:26703928

  6. Role of Erbin in ErbB2-dependent breast tumor growth

    PubMed Central

    Tao, Yanmei; Shen, Chengyong; Luo, Shiwen; Traoré, Wilfried; Marchetto, Sylvie; Santoni, Marie-Josée; Xu, Linlin; Wu, Biao; Shi, Chao; Mei, Jinghong; Bates, Ryan; Liu, Xihui; Zhao, Kai; Xiong, Wen-Cheng; Borg, Jean-Paul; Mei, Lin

    2014-01-01

    ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression. PMID:25288731

  7. A superpixel-based framework for automatic tumor segmentation on breast DCE-MRI

    NASA Astrophysics Data System (ADS)

    Yu, Ning; Wu, Jia; Weinstein, Susan P.; Gaonkar, Bilwaj; Keller, Brad M.; Ashraf, Ahmed B.; Jiang, YunQing; Davatzikos, Christos; Conant, Emily F.; Kontos, Despina

    2015-03-01

    Accurate and efficient automated tumor segmentation in breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is highly desirable for computer-aided tumor diagnosis. We propose a novel automatic segmentation framework which incorporates mean-shift smoothing, superpixel-wise classification, pixel-wise graph-cuts partitioning, and morphological refinement. A set of 15 breast DCE-MR images, obtained from the American College of Radiology Imaging Network (ACRIN) 6657 I-SPY trial, were manually segmented to generate tumor masks (as ground truth) and breast masks (as regions of interest). Four state-of-the-art segmentation approaches based on diverse models were also utilized for comparison. Based on five standard evaluation metrics for segmentation, the proposed framework consistently outperformed all other approaches. The performance of the proposed framework was: 1) 0.83 for Dice similarity coefficient, 2) 0.96 for pixel-wise accuracy, 3) 0.72 for VOC score, 4) 0.79 mm for mean absolute difference, and 5) 11.71 mm for maximum Hausdorff distance, which surpassed the second best method (i.e., adaptive geodesic transformation), a semi-automatic algorithm depending on precise initialization. Our results suggest promising potential applications of our segmentation framework in assisting analysis of breast carcinomas.

  8. Photoacoustic imaging of breast tumor vascularization: a comparison with MRI and histopathology

    NASA Astrophysics Data System (ADS)

    Heijblom, Michelle; Piras, Daniele; van den Engh, Frank M.; Klaase, Joost M.; Brinkhuis, Mariël.; Steenbergen, Wiendelt; Manohar, Srirang

    2013-06-01

    Breast cancer is the most common form of cancer and the leading cause of cancer death among females. Early diagnosis improves the survival chances for the disease and that is why there is an ongoing search for improved methods for visualizing breast cancer. One of the hallmarks of breast cancer is the increase in tumor vascularization that is associated with angiogenesis: a crucial factor for survival of malignancies. Photoacoustic imaging can visualize the malignancyassociated increased hemoglobin concentration with optical contrast and ultrasound resolution, without the use of ionizing radiation or contrast agents and is therefore theoretically an ideal method for breast imaging. Previous clinical studies using the Twente Photoacoustic Mammoscope (PAM), which works in forward mode using a single wavelength (1064 nm), showed that malignancies can indeed be identified in the photoacoustic imaging volume as high contrast areas. However, the specific appearance of the malignancies led to questions about the contrast mechanism in relation to tumor vascularization. In this study, the photoacoustic lesion appearance obtained with an updated version of PAM is compared with the lesion appearance on Magnetic Resonance Imaging (MRI), both in general (19 patients) and on an individual basis (7 patients). Further, in 3 patients an extended histopathology protocol is being performed in which malignancies are stained for vascularity using an endothelial antibody: CD31. The correspondence between PAM and MRI and between PAM and histopathology makes it likely that the high photoacoustic contrast at 1064 nm is indeed largely the consequence of the increased tumor vascularization.

  9. Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer

    PubMed Central

    Miwa, Hazuki E; Koba, Wade R; Fine, Eugene J; Giricz, Orsi; Kenny, Paraic A; Stanley, Pamela

    2013-01-01

    Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the mouse mammary tumor virus (MMTV) promoter. However, the penetrance of the tumor phenotype became variable in mixed FVB/N and C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3−/−/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3−/−/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors and lung metastasis. Nevertheless, activation of extracellular signal-regulated kinase (ERK)1/2 or protein kinase B (AKT) was reduced in ∼20-week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of focal adhesion kinase (FAK), protein tyrosine kinase Src, and p38 mitogen-activated protein kinase were similar to that of controls. All the eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least 10 galectin and 7 N-glycan N-acetylglucosaminyl (GlcNAc)-transferase (MGAT) genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identification of key galectins that promote mammary tumor progression in mice is not straightforward because all the eight galectin genes are expressed; and high levels of MGAT3, galectin-4, -8, -10, -13 and -14 transcripts correlate with better relapse-free survival in human breast cancer. PMID:24037315

  10. Associations between Polycyclic Aromatic Hydrocarbon–Related Exposures and p53 Mutations in Breast Tumors

    PubMed Central

    Mordukhovich, Irina; Rossner, Pavel; Terry, Mary Beth; Santella, Regina; Zhang, Yu-Jing; Hibshoosh, Hanina; Memeo, Lorenzo; Mansukhani, Mahesh; Long, Chang-Min; Garbowski, Gail; Agrawal, Meenakshi; Gaudet, Mia M.; Steck, Susan E.; Sagiv, Sharon K.; Eng, Sybil M.; Teitelbaum, Susan L.; Neugut, Alfred I.; Conway-Dorsey, Kathleen; Gammon, Marilie D.

    2010-01-01

    Background Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. Objectives We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. Methods We examined this possibility in a population-based case–control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. Results We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH–DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation–negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11–2.15] but not p53 mutation–positive (OR = 0.77; 95% CI, 0.43–1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C→A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. Conclusions These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation. PMID:20064791

  11. Surface-enhanced Raman spectroscopy of saliva proteins for the noninvasive differentiation of benign and malignant breast tumors

    PubMed Central

    Feng, Shangyuan; Huang, Shaohua; Lin, Duo; Chen, Guannan; Xu, Yuanji; Li, Yongzeng; Huang, Zufang; Pan, Jianji; Chen, Rong; Zeng, Haishan

    2015-01-01

    The capability of saliva protein analysis, based on membrane protein purification and surface-enhanced Raman spectroscopy (SERS), for detecting benign and malignant breast tumors is presented in this paper. A total of 97 SERS spectra from purified saliva proteins were acquired from samples obtained from three groups: 33 healthy subjects; 33 patients with benign breast tumors; and 31 patients with malignant breast tumors. Subtle but discernible changes in the mean SERS spectra of the three groups were observed. Tentative assignments of the saliva protein SERS spectra demonstrated that benign and malignant breast tumors led to several specific biomolecular changes of the saliva proteins. Multiclass partial least squares–discriminant analysis was utilized to analyze and classify the saliva protein SERS spectra from healthy subjects, benign breast tumor patients, and malignant breast tumor patients, yielding diagnostic sensitivities of 75.75%, 72.73%, and 74.19%, as well as specificities of 93.75%, 81.25%, and 86.36%, respectively. The results from this exploratory work demonstrate that saliva protein SERS analysis combined with partial least squares–discriminant analysis diagnostic algorithms has great potential for the noninvasive and label-free detection of breast cancer. PMID:25609959

  12. Pseudoangio-matous stromal hyperplasia: A rare tumor of the breast.

    PubMed

    Shahi, Kedar Singh; Bhandari, Geeta; Gupta, Rakesh Kumar; Sawai, Malvika

    2015-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast entity described first by Vuitch et al., in 1986. PASH is a benign stromal lesion containing complex anastomosing channels lined by slender spindle cells. It can be mistaken with fibroadenoma on ultrasound examination and histologically with low-grade angiosarcoma and phyllodes tumor. Here, presented is a case report of a 30-year-old female who presented with huge palpable lump in left breast. Ultrasonography revealed the lesion as giant fibroadenoma and fine needle aspiration cytology report was suggestive of cystosarcoma phyllodes. Excision and reduction mammoplasty was done and histopathology report was suggestive of PASH. PMID:26881624

  13. Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer

    PubMed Central

    Bierie, Brian; Chung, Christine H.; Parker, Joel S.; Stover, Daniel G.; Cheng, Nikki; Chytil, Anna; Aakre, Mary; Shyr, Yu; Moses, Harold L.

    2009-01-01

    In human breast cancer, loss of carcinoma cell–specific response to TGF-β signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-β regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-β signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-β signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M–induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-β–associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-β signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor–positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-β signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer. PMID:19451693

  14. The Dynamic Tumor Bed: Volumetric Changes in the Lumpectomy Cavity During Breast-Conserving Therapy

    SciTech Connect

    Prendergast, Brendan; Indelicato, Daniel J. Grobmyer, Stephen R.; Saito, Anneyuko I.; Lightsey, Judith L.; Snead, Felicia E.; Morris, Christopher G.; Copeland, Edward M.; Mendenhall, Nancy P.

    2009-07-01

    Purpose: To characterize the magnitude of volume change in the postoperative tumor bed before and during radiotherapy, and to identify any factors associated with large volumetric change. Methods and Materials: Thirty-six consecutive patients with early-stage or preinvasive breast cancer underwent breast-conserving therapy at our institution between June 2006 and October 2007. Computed tomography (CT) scans of the breast were obtained shortly after surgery, before the start of radiotherapy (RT) for treatment planning, and, if applicable, before the tumor bed boost. Postoperative changes, seroma, and surgical clips were used to define the tumor bed through consensus agreement of 3 observers (B.P., D.I., and J.L.). Multiple variables were examined for correlation with volumetric change. Results: Between the first and last scan obtained (median time, 7.2 weeks), the tumor bed volume decreased at least 20% in 86% of patients (n = 31) and at least 50% in 64% of patients (n = 23). From the postoperative scan to the planning scan (median time, 3 weeks), the tumor bed volume decreased by an average of 49.9%, or approximately 2.1% per postoperative day. From planning scan to boost scan (median interval, 7 weeks), the median tumor bed volume decreased by 44.6%, at an average rate of 0.95% per postoperative day. No single factor was significantly associated with a change in tumor bed volume greater than 20%. Conclusions: The average postlumpectomy cavity undergoes dramatic volumetric change after surgery and continues this change during RT. The rate of change is inversely proportional to the duration from surgery. In this study no factors studied predicted large volumetric change.

  15. Metastatic Breast Carcinoma to the Prostate Gland.

    PubMed

    Kapp, Meghan E; Giannico, Giovanna A; Desouki, Mohamed Mokhtar

    2016-01-01

    Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors. PMID:27429817

  16. Metastatic Breast Carcinoma to the Prostate Gland

    PubMed Central

    Kapp, Meghan E.

    2016-01-01

    Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors. PMID:27429817

  17. Use of Raman Spectroscopy in Characterizing Formalin-Fixed, Paraffin-Embedded Breast Tumor Samples (abstract)

    NASA Astrophysics Data System (ADS)

    Downey, Frances; Cade, Nicholas; Cook, Richard; Springall, Robert; Gillet, Cheryl; Richards, David; Festy, Frederic

    2009-04-01

    Formalin-fixed, paraffin-embedded (FFPE) sections of breast tissue are used by pathologists to correctly type and grade the primary tumor and to assess the extent of a patient's disease. The cut sections represent a reproducible likeness of the morphology of the tissue when viewed through a microscope, although the fixation technique creates some artifacts. What is not known is how the sections differ chemically from how the tumor would look or behave within the breast. Raman spectroscopy is, like many other optical techniques, fast, noninvasive, and generally inexpensive. The advantage Raman has over other techniques is its powerful ability to identify specific chemicals, molecules, and bonds within a sample. Using Raman spectroscopy the chemicals present in both fresh tissue and FFPE sections can be identified and compared, allowing any differences between them to be identified. This information may be useful to the pathologist as an aid to further treatment regimes or novel molecular techniques, and as an aid to patient management. If these sections are found to be chemically similar to fresh tissue, they could be used to further characterize breast tumors, particularly rare tumors, using Raman spectroscopy.

  18. Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration

    SciTech Connect

    Heering, Johanna; Erlmann, Patrik; Olayioye, Monilola A.

    2009-09-10

    The phosphatase and tensin homolog (PTEN) gene is a tumor suppressor frequently deleted or mutated in sporadic tumors of the breast, prostate, endometrium and brain. The protein acts as a dual specificity phosphatase for lipids and proteins. PTEN loss confers a growth advantage to cells, protects from apoptosis and favors cell migration. The deleted in liver cancer 1 (DLC1) gene has emerged as a novel tumor suppressor downregulated in a variety of tumor types including those of the breast. DLC1 contains a Rho GTPase activating domain that is involved in the inhibition of cell proliferation, migration and invasion. To investigate how simultaneous loss of PTEN and DLC1 contributes to cell transformation, we downregulated both proteins by RNA interference in the non-invasive MCF7 breast carcinoma cell line. Joint depletion of PTEN and DLC1 resulted in enhanced cell migration in wounding and chemotactic transwell assays. Interestingly, both proteins were found to colocalize at the plasma membrane and interacted physically in biochemical pulldowns and coimmunoprecipitations. We therefore postulate that the concerted local inactivation of signaling pathways downstream of PTEN and DLC1, respectively, is required for the tight control of cell migration.

  19. Development of spectrophotometer for breast tumor diagnostic spectrometer based on virtual instruments

    NASA Astrophysics Data System (ADS)

    Ren, Zhong; Liu, Guodong; Liu, Ying; Huang, Zhen

    2013-12-01

    Although some progresses have been achieved by the traditional diagnostic methods, such as X mammography, computer tomography (CT) imaging and magnetic resonance imaging (MRI) etc, their applications are limited by some drawbacks to some extent. As a more promising alternative method, the breast tumor diagnosis method based on infrared spectrometer was introduced. According to the theory of spectral unique characteristics for matter, i.e. the spectrums are different for the matter with different properties, so the spectrums are different between the tumor and normal tissues. Therefore, a spectrometer system was developed to diagnose the breast tumor in this paper. Meanwhile, a spectrophotometer for breast tumor diagnostic spectrometer was designed, and the plane holography concave (PHV) grating was used as the dispersion device in this spectrophotometer because of excellent performances. In this system, linear CCD detector combined with PCI data acquisition card was used as the spectral detector, and the virtual instruments (VI) technique was used to control the data acquisition and data processing. In experiments, the spectral calibration based on mercury lamp was performed. Experimental results illustrated that the construction of the spectrophotometer system is available, the spectral range is from 300-850nm, its wavelength resolution reached 2nm. The simulation experimental result proved that the design of the diagnostic system was very satisfied and diagnostic method was also feasible.

  20. GPER is involved in the stimulatory effects of aldosterone in breast cancer cells and breast tumor-derived endothelial cells.

    PubMed

    Rigiracciolo, Damiano Cosimo; Scarpelli, Andrea; Lappano, Rosamaria; Pisano, Assunta; Santolla, Maria Francesca; Avino, Silvia; De Marco, Paola; Bussolati, Benedetta; Maggiolini, Marcello; De Francesco, Ernestina Marianna

    2016-01-01

    Aldosterone induces relevant effects binding to the mineralcorticoid receptor (MR), which acts as a ligand-gated transcription factor. Alternate mechanisms can mediate the action of aldosterone such as the activation of epidermal growth factor receptor (EGFR), MAPK/ERK, transcription factors and ion channels. The G-protein estrogen receptor (GPER) has been involved in the stimulatory effects of estrogenic signalling in breast cancer. GPER has been also shown to contribute to certain responses to aldosterone, however the role played by GPER and the molecular mechanisms implicated remain to be fully understood. Here, we evaluated the involvement of GPER in the stimulatory action exerted by aldosterone in breast cancer cells and breast tumor derived endothelial cells (B-TEC). Competition assays, gene expression and silencing studies, immunoblotting and immunofluorescence experiments, cell proliferation and migration were performed in order to provide novel insights into the role of GPER in the aldosterone-activated signalling. Our results demonstrate that aldosterone triggers the EGFR/ERK transduction pathway in a MR- and GPER-dependent manner. Aldosterone does not bind to GPER, it however induces the direct interaction between MR and GPER as well as between GPER and EGFR. Next, we ascertain that the up-regulation of the Na+/H+ exchanger-1 (NHE-1) induced by aldosterone involves MR and GPER. Biologically, both MR and GPER contribute to the proliferation and migration of breast and endothelial cancer cells mediated by NHE-1 upon aldosterone exposure. Our data further extend the current knowledge on the molecular mechanisms through which GPER may contribute to the stimulatory action elicited by aldosterone in breast cancer. PMID:26646587

  1. GPER is involved in the stimulatory effects of aldosterone in breast cancer cells and breast tumor-derived endothelial cells

    PubMed Central

    Rigiracciolo, Damiano Cosimo; Scarpelli, Andrea; Lappano, Rosamaria; Pisano, Assunta; Santolla, Maria Francesca; Avino, Silvia; De Marco, Paola; Bussolati, Benedetta; Maggiolini, Marcello; De Francesco, Ernestina Marianna

    2016-01-01

    Aldosterone induces relevant effects binding to the mineralcorticoid receptor (MR), which acts as a ligand-gated transcription factor. Alternate mechanisms can mediate the action of aldosterone such as the activation of epidermal growth factor receptor (EGFR), MAPK/ERK, transcription factors and ion channels. The G-protein estrogen receptor (GPER) has been involved in the stimulatory effects of estrogenic signalling in breast cancer. GPER has been also shown to contribute to certain responses to aldosterone, however the role played by GPER and the molecular mechanisms implicated remain to be fully understood. Here, we evaluated the involvement of GPER in the stimulatory action exerted by aldosterone in breast cancer cells and breast tumor derived endothelial cells (B-TEC). Competition assays, gene expression and silencing studies, immunoblotting and immunofluorescence experiments, cell proliferation and migration were performed in order to provide novel insights into the role of GPER in the aldosterone-activated signalling. Our results demonstrate that aldosterone triggers the EGFR/ERK transduction pathway in a MR- and GPER-dependent manner. Aldosterone does not bind to GPER, it however induces the direct interaction between MR and GPER as well as between GPER and EGFR. Next, we ascertain that the up-regulation of the Na+/H+ exchanger-1 (NHE-1) induced by aldosterone involves MR and GPER. Biologically, both MR and GPER contribute to the proliferation and migration of breast and endothelial cancer cells mediated by NHE-1 upon aldosterone exposure. Our data further extend the current knowledge on the molecular mechanisms through which GPER may contribute to the stimulatory action elicited by aldosterone in breast cancer. PMID:26646587

  2. Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

    PubMed Central

    2014-01-01

    Introduction BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. Results Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH tumors were ER-positive. Conclusions Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen

  3. Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy

    SciTech Connect

    Aghaei, Faranak; Tan, Maxine; Liu, Hong; Zheng, Bin; Hollingsworth, Alan B.; Qian, Wei

    2015-11-15

    Purpose: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. Methods: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. Results: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC = 0.85 ± 0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96 ± 0.03 (p < 0.01). Conclusions: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy.

  4. MTUS1 tumor suppressor and its miRNA regulators in fibroadenoma and breast cancer.

    PubMed

    Kara, Murat; Kaplan, Mehmet; Bozgeyik, Ibrahim; Ozcan, Onder; Celik, Ozgur Ilhan; Bozgeyik, Esra; Yumrutas, Onder

    2016-08-10

    Breast cancer is major public health problem predominantly effects female population. Current therapeutic approaches to deal with breast cancer are still lack of effectiveness. Thus, identifying/developing novel strategies to fight against breast cancer is very important. The frequent deletions at 8p21.3-22 chromosomal location nearby D8S254 marker enabled the discovery of a novel tumor suppressor gene, MTUS1. Subsequently, MTUS1 was demonstrated to be less expressed in a variety cancer types including breast cancer. Also, it is obvious that gene expression is widely regulated by miRNAs. Here, we aimed to report differential expression of MTUS1 and its regulatory miRNAs in breast cancer and fibroadenoma tissues. Dynamic analysis of MTUS1 expression levels and its miRNAs regulators were attained by Fluidigm 96×96 Dynamic Array Expression chips and reactions were performed in Fluidigm BioMark™ HD System qPCR. Consequently, MTUS1 mRNA levels were significantly diminished in breast cancer tissues and elevated in fibroadenoma tissues. Also, among MTUS1 targeting miRNAs, miR-183-5p was identified to be overexpressed in breast cancer and down-regulated in fibroadenoma tissues. Also, expression levels of MTUS1 and miR-183-5p were well correlated with clinical parameters. In particular, MTUS1 expression was found to be diminished and miR-183-5p expression was elevated with the advancing stage. In conclusion, as a potential therapeutic target, miR-183-5p can be a chief regulator of MTUS1 and MTUS1-miR-183-5p axis may have significant influence in the pathology of breast cancer. PMID:27155522

  5. Planning the Breast Boost: Comparison of Three Techniques and Evolution of Tumor Bed During Treatment

    SciTech Connect

    Hepel, Jaroslaw T. Evans, Suzanne B.; Hiatt, Jessica R.; Price, Lori Lyn; DiPetrillo, Thomas; Wazer, David E.; MacAusland, Stephanie G.

    2009-06-01

    Purpose: To evaluate the accuracy of two clinical techniques for electron boost planning compared with computed tomography (CT)-based planning. Additionally, we evaluated the tumor bed characteristics at whole breast planning and boost planning. Methods and Materials: A total of 30 women underwent tumor bed boost planning within 2 weeks of completing whole breast radiotherapy using three planning techniques: scar-based planning, palpation/clinical-based planning, and CT-based planning. The plans were analyzed for dosimetric coverage of the CT-delineated tumor bed. The cavity visualization score was used to define the CT-delineated tumor bed as well or poorly defined. Results: Scar-based planning resulted in inferior tumor bed coverage compared with CT-based planning, with the minimal dose received by 90% of the target volume >90% in 53% and a geographic miss in 53%. The results of palpation/clinical-based planning were significantly better: 87% and 10% for the minimal dose received by 90% of the target volume >90% and geographic miss, respectively. Of the 30 tumor beds, 16 were poorly defined by the cavity visualization score. Of these 16, 8 were well demarcated by the surgical clips. The evaluation of the 22 well-defined tumor beds revealed similar results. A comparison of the tumor bed volume from the initial planning CT scan to the boost planning CT scan revealed a decrease in size in 77% of cases. The mean decrease in volume was 52%. Conclusion: The results of our study have shown that CT-based planning allows for optimal tumor bed coverage compared with clinical and scar-based approaches. However, in the setting of a poorly visualized cavity on CT without surgical clips, palpation/clinical-based planning can help delineate the appropriate target volumes and is superior to scar-based planning. CT simulation at boost planning could allow for a reduction in the boost volumes.

  6. Early identification of non-responding locally advanced breast tumors receiving neoadjuvant chemotherapy

    NASA Astrophysics Data System (ADS)

    Van de Giessen, Martijn; Schaafsma, Boudewijn E.; Charehbili, Ayoub; Smit, Vincent T. H. B. M.; Kroep, Judith R.; Lelieveldt, Boudewijn P. F.; Liefers, Gerrit-Jan; Chan, Alan; Löwik, Clemens W. G. M.; Dijkstra, Jouke; van de Velde, Cornelis J. H.; Wasser, Martin N. J. M.; Vahrmeijer, Alexander L.

    2015-02-01

    Diffuse optical spectroscopy (DOS) may be advantageous for monitoring tumor response during chemotherapy treatment, particularly in the early treatment stages. In this paper we perform a second analysis on the data of a clinical trial with 25 breast cancer patients that received neoadjuvant chemotherapy. Patients were monitored using delayed contrast enhanced MRI and additionally with diffuse optical spectroscopy at baseline, after 1 cycle of chemotherapy, halfway therapy and before surgery. In this analysis hemoglobin content between tumor tissue and healthy tissue of the same breast is compared on all four monitoring time points. Furthermore, the predictive power of the tumor-healthy tissue difference of HbO2 for non-responder prediction is assessed. The difference in HbO2 content between tumor and healthy tissue was statistically significantly higher in responding tumors than in non-responding tumors at baseline (10.88 vs -0.57 μM, P=0.014) and after one cycle of chemotherapy (6.45 vs -1.31 μM, P=0.048). Before surgery this difference had diminished. In the data of this study, classification on the HbO2 difference between tumor and healthy tissue was able to predict tumor (non-)response at baseline and after 1 cycle with an area-under-curve of 0.95 and 0.88, respectively. While this result suggests that tumor response can be predicted before chemotherapy onset, one should be very careful with interpreting these results. A larger patient population is needed to confirm this finding.

  7. Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D.

    PubMed

    Jeong, Youngtae; Swami, Srilatha; Krishnan, Aruna V; Williams, Jasmaine D; Martin, Shanique; Horst, Ronald L; Albertelli, Megan A; Feldman, Brian J; Feldman, David; Diehn, Maximilian

    2015-08-01

    The anticancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and preclinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here, we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors and estrogen receptors (ER) and exhibited calcitriol-induced molecular responses including ER downregulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth, whereas a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies may enhance anticancer activity and improve therapeutic outcomes. PMID:25934710

  8. Connexin 43, breast cancer tumor suppressor: Missed connections?

    PubMed

    Grek, Christina L; Rhett, J Matthew; Bruce, Jaclynn S; Ghatnekar, Gautam S; Yeh, Elizabeth S

    2016-04-28

    Connexins are a family of transmembrane proteins that are characterized by their capacity to form intercellular channels called gap junctions that directly link the cytoplasm of adjacent cells. The formation of gap junctions by connexin proteins facilitates intercellular communication between neighboring cells by allowing for the transfer of ions and small signaling molecules. Communication through gap junctions is key to cellular equilibrium, where connexins, and the gap junction intercellular communication that connexins propagate, have roles in cellular processes such as cell growth, differentiation, and tissue homeostasis. Due to their importance in maintaining cellular functions, the disruption of connexin expression and function underlies the etiology and progression of numerous pathologies, including cancer. Over the past half a century, the role of connexins and gap junction intercellular communication have been highlighted as critical areas of research in cellular malignancies, and much research effort has been geared toward understanding their dysfunction in human cancers. Although ample evidence supports the role of connexins in a variety of human cancers, detailed examination in specific cancers, such as breast cancer, is still lacking. This review highlights the most abundant gap junction connexin isoform in higher vertebrate organisms, Connexin 43, and its role in breast cancer. PMID:26884256

  9. No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women

    NASA Astrophysics Data System (ADS)

    Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L. E.; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A.; Torres, Javier; Fuentes-Pananá, Ezequiel M.

    2013-10-01

    Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer.

  10. Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors

    PubMed Central

    Schwab, Richard; Harismendy, Olivier; Pu, Minya; Crain, Brian; Yost, Shawn; Frazer, Kelly A.; Rana, Brinda; Hasteh, Farnaz; Wallace, Anne; Parker, Barbara A.

    2015-01-01

    Background Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations). Methods Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas. Results We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value <0.01), across renal cell, testicular, and colorectal cancer. The CLS test correctly classified all validation samples but one, which it appears may have been incorrectly classified in the published data. As proof-of-concept we then applied the CLS test to two new cases of invasive synchronous bilateral breast cancer at our institution, each with one hormone receptor positive (ER+/PR+/HER2-) lobular and one triple negative ductal carcinoma. High confidence mutations were identified by exome sequencing and results were validated using deep targeted sequencing. The first tumor pair had CLS of 81% (p-value < 10–15), supporting clonality. In the second pair, no common mutations of 184 variants were validated (p-value >0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the

  11. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    PubMed

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX. PMID:26071407

  12. Differential regulation and function of tumor-infiltrating T cells in different stages of breast cancer patients.

    PubMed

    Zhu, Shiguang; Lin, Jun; Qiao, Guangdong; Xu, Yanping; Zou, Haidong

    2015-09-01

    Breast cancer survival was associated with higher frequencies of CD8(+) T cytotoxic T cells in infiltrating lymphocytes. On the other hand, the frequency of CD4(+)CD25(+)FoxP3(+) regulatory T cells was inversely correlated with clinical outcomes of breast cancer. The regulation and interaction of different types of tumor-infiltrating T cells in different stages of breast cancer patients are still unclear. In this study, we examined the functions and regulations of CD8(+) T cells and CD4(+)CD25(+)FoxP3(+) T cells from resected tumors from 12 stage I, 24 stage II, and 20 stage III untreated breast cancer patients. We found that tumor-infiltrating CD8(+) T cells from stage III patients were more refractory to T cell receptor (TCR) stimulation than those from stage I and stage II patients in terms of interferon gamma (IFN-γ) production and proliferation. On the other hand, tumor-infiltrating CD4(+)CD25(+)FoxP3(+) T cells had higher proliferation in stage III tumors than in stage I and stage II tumors. In addition, we found that tumor-infiltrating CD4(+)CD25(+) T cells can suppress CD8(+) T cell inflammation ex vivo. Altogether, our data demonstrated that stage III tumors in breast cancer patients had a more immunosuppressive microenvironment. PMID:25953262

  13. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

    PubMed

    Horne, Hisani N; Chung, Charles C; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H; Ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Vachon, Celine; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Marchand, Loic Le; Goldberg, Mark S; Teo, Soo H; Taib, Nur A M; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W M; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D P; Easton, Douglas F; Chanock, Stephen J; Dunning, Alison M; Figueroa, Jonine D

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. PMID:27556229

  14. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

    PubMed Central

    Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Marchand, Loic Le; Goldberg, Mark S.; Teo, Soo H.; Taib, Nur A. M.; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W. M.; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D. P.

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. PMID:27556229

  15. Distribution of MED12 mutations in fibroadenomas and phyllodes tumors of the breast--implications for tumor biology and pathological diagnosis.

    PubMed

    Pfarr, Nicole; Kriegsmann, Mark; Sinn, Peter; Klauschen, Frederick; Endris, Volker; Herpel, Esther; Muckenhuber, Alexander; Jesinghaus, Moritz; Klosterhalfen, Bernd; Penzel, Roland; Lennerz, Jochen K; Weichert, Wilko; Stenzinger, Albrecht

    2015-07-01

    Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare. PMID:25931199

  16. [The degree of tumor vascularization as a prognostic factor of the efficacy of neoadjuvant polychemotherapy in breast cancer].

    PubMed

    Voznyĭ, E K; Biakhov, M Iu; Gorb, A I; Krivenko, E V; Chkhikvadze, V D; Alipchenko, L A; Agrinskaia, I A

    1992-01-01

    A procedure for obtaining microcirculation coefficient is described. It is based on the phenomenon of formation of a focus of radionuclide hyperfixation on scintigrams of tumor area due to embolization of its arterioles and precapillaries with radionuclide. The method was used in 26 breast cancer patients before neoadjuvant chemotherapy. A direct correlation between the microcirculation coefficient and degree of tumor-induced pathomorphosis of tumor cells was established. The coefficient values proved more or less predictive of tumor response to chemotherapy. PMID:1338674

  17. A three dimensional micropatterned tumor model for breast cancer cell migration studies.

    PubMed

    Peela, Nitish; Sam, Feba S; Christenson, Wayne; Truong, Danh; Watson, Adam W; Mouneimne, Ghassan; Ros, Robert; Nikkhah, Mehdi

    2016-03-01

    Breast cancer cell invasion is a highly orchestrated process driven by a myriad of complex microenvironmental stimuli, making it difficult to isolate and assess the effects of biochemical or biophysical cues (i.e. tumor architecture, matrix stiffness) on disease progression. In this regard, physiologically relevant tumor models are becoming instrumental to perform studies of cancer cell invasion within well-controlled conditions. Herein, we explored the use of photocrosslinkable hydrogels and a novel, two-step photolithography technique to microengineer a 3D breast tumor model. The microfabrication process enabled precise localization of cell-encapsulated circular constructs adjacent to a low stiffness matrix. To validate the model, breast cancer cell lines (MDA-MB-231, MCF7) and non-tumorigenic mammary epithelial cells (MCF10A) were embedded separately within the tumor model, all of which maintained high viability throughout the experiments. MDA-MB-231 cells exhibited extensive migratory behavior and invaded the surrounding matrix, whereas MCF7 or MCF10A cells formed clusters that stayed confined within the circular tumor regions. Additionally, real-time cell tracking indicated that the speed and persistence of MDA-MB-231 cells were substantially higher within the surrounding matrix compared to the circular constructs. Z-stack imaging of F-actin/α-tubulin cytoskeletal organization revealed unique 3D protrusions in MDA-MB-231 cells and an abundance of 3D clusters formed by MCF7 and MCF10A cells. Our results indicate that gelatin methacrylate (GelMA) hydrogel, integrated with the two-step photolithography technique, has great promise in the development of 3D tumor models with well-defined architecture and tunable stiffness. PMID:26724455

  18. Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer.

    PubMed

    Paauwe, M; Heijkants, R C; Oudt, C H; van Pelt, G W; Cui, C; Theuer, C P; Hardwick, J C H; Sier, C F M; Hawinkels, L J A C

    2016-08-01

    Endoglin, a transforming growth factor-β co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo. PMID:26804178

  19. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor.

    PubMed

    Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Dehghan, Mohammad Javad; Khori, Vahid; Heidarzadeh, Alemeh; Khaniki, Mahmood; Sadeghiezadeh, Majid; Najafi, Farhood

    2015-07-01

    Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24h (P<0.05). Under the dosing procedure, DNC was safe at 80mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27cm(3) in the control, and 40 and 80mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products. PMID:25863259

  20. Management and Reconstruction in the Breast Cancer Patient With a Fungating T4b Tumor

    PubMed Central

    Daniali, Lily N.; Rezzadeh, Kameron S.; Lee, Edward S.; Keith, Jonathan

    2015-01-01

    Background: A subset of women with locally advanced breast cancer presented with fungating tumor mass eroding and infiltrating the surrounding breast skin (T4b breast cancers). These patients often have chronic pain, large open wounds, frequent infections, malodorous drainage, social isolation, and general debilitation that present enormous therapeutic challenges. Because of the advanced nature of the disease, palliation, while minimizing recovery time and maximizing quality of life, is essential. Methods: From 2009 to 2014, a total of 12 consecutive patients underwent resection of fungating T4b breast tumors and subsequent chest wall reconstruction. Demographic, socioeconomic, and clinical data were collected retrospectively. Results: Fifty percent of women had distant metastases at the time of reconstruction, and 17% of women presented to the emergency department in a hemodynamically unstable condition in either hemorrhagic shock or septic shock, necessitating delay of reconstruction for up to 1 week. Mean wound size for reconstruction was 473 cm2. Reconstructive procedures included split-thickness skin grafting and thoracoepigastric advancement, latissimus dorsi, trapezius, and extended transverse and vertical rectus abdominis flaps. Postoperative survival ranged from 98 to 172 days (mean = 127 days), with 9 patients currently living. Seventy-five percent of patients had improved pain and reduced wound care needs after reconstruction. Postoperative reconstruction-specific complications occurred in 33% of cases, with 1 patient requiring a second operating room visit. Conclusions: Women with fungating T4b breast cancer tumors often present with metastatic disease and have significant need for pain and wound palliation. The reconstructive techniques performed are reliable, efficacious in palliating pain, and reducing wound care needs and have low complication rates. PMID:26417396

  1. Multifocal Tumorous Pseudoangiomatous Stromal Hyperplasia Presenting as Asymmetric Bilateral Breast Enlargement

    PubMed Central

    Vasconcelos, I.; Perez Fernandez, C. M.; Günzel, S.; Schoenegg, W.

    2015-01-01

    PASH is a benign proliferation of stromal myofibroblasts that affects mostly premenopausal women and typically shows estrogen and progesterone receptor expression, allowing speculation regarding a hormonal cause. It usually presents as an incidental finding on a mammogram or as a palpable mass. We present a case of diffuse asymmetrical massive breast enlargement in a premenopausal woman with history of previous multiple PASH excisions for recurrent lesions, caused by multifocal tumorous PASH virtually replacing the breast parenchyma. Immunohistochemistry examination showed no hormone receptor expression. Despite its benign nature, such presentation of PASH is managed with bilateral mastectomy and immediate reconstruction with expanders for cosmetic and comfort reasons, while tumor excision or expectant management is deemed to lead to recurrence and progression. Although a hormonal origin is speculated based on hormone expression studies and typical patient profile, this case showed 0 % estrogen/progesterone expression in the final histology specimen. PMID:25797961

  2. Interferogram-based breast tumor classification using microwave-induced thermoacoustic imaging.

    PubMed

    Hao Nan; Haghi, Benyamin Allahgholizadeh; Arbabian, Amin

    2015-08-01

    Microwave-induced thermoacoustic (TA) imaging combines the dielectric/conductivity contrast in the microwave range with the high resolution of ultrasound imaging. Lack of ionizing radiation exposure in TA imaging makes this technique suitable for frequent screening applications, as with breast cancer screening. In this paper we demonstrate breast tumor classification based on TA imaging. The sensitivity of the signal-based classification algorithm to errors in the estimation of tumor locations is investigated. To reduce this sensitivity, we propose to use the interferogram of received pressure waves as the feature basis used for classification, and demonstrate the robustness based on a finite-difference time-domain (FDTD) simulation framework. PMID:26736853

  3. Modulation of Efector Caspase Cleavage Determines Response of Breast and Lung Tumor Cell Lines to Chemotherapy

    PubMed Central

    Odonkor, Charles Amoatey; Achilefu, Samuel

    2010-01-01

    In spite of compelling evidence implicating caspases in drug-induced apoptosis, how tumors modulate caspase expression and activity to overcome the cytotoxicity of anticancer agents is not fully understood. To address this issue, we investigated the role of caspases-3 and 7 in determining the response of breast and lung tumor cell lines to chemotherapy. We found that an early and late apoptotic response correlated with weak and strong cellular caspase-activation, respectively. The results highlight an underappreciated relationship of temporal apoptotic response with caspase-activation and drug-resistance. Moreover, the extent of tumor growth restoration after drug withdrawal was dependent on the degree of endogenous blockage of caspase-3 and caspase-7 cleavages. This points to an unrecognized role of caspase modulation in tumor recurrence and suggests that targeting caspase cleavage is a rational approach to increasing potency of cancer drugs. PMID:19241192

  4. Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells.

    PubMed

    Braune, Eike-Benjamin; Tsoi, Yat Long; Phoon, Yee Peng; Landor, Sebastian; Silva Cascales, Helena; Ramsköld, Daniel; Deng, Qiaolin; Lindqvist, Arne; Lian, Xiaojun; Sahlgren, Cecilia; Jin, Shao-Bo; Lendahl, Urban

    2016-05-10

    Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response. PMID:27066863

  5. Phylloides tumor of the breast: a report of 14 cases.

    PubMed

    Hopkins, M L; McGowan, T S; Rawlings, G; Liu, F F; Fyles, A W; Yeoh, J L; Manchul, L; Levin, W

    1994-06-01

    The objective of this retrospective study is to determine the role of radiation therapy in the management of benign phylloides tumors. Fourteen patients with a diagnosis of benign phylloides tumor (PT) and registered at the Princess Margaret Hospital are included in the study. Definitive surgery consisted of either lumpectomy in seven patients or mastectomy in the other seven patients. One patient died of her disease, and the remaining patients had no evidence of disease at last follow-up (median 38.4 months). Among these 13 patients, 4 had at least one recurrence and the recurrence rate was higher for the group who underwent lumpectomy (43% compared with 28%). One patient was treated by lumpectomy and adjuvant radiation therapy, and had no subsequent recurrence (follow-up time 35.5 months). The role for radiation therapy in the management of this disease remains unclear. PMID:8007675

  6. A Bioimage Informatics Based Reconstruction of Breast Tumor Microvasculature with Computational Blood Flow Predictions

    PubMed Central

    Stamatelos, Spyros K.; Kim, Eugene; Pathak, Arvind P.; Popel, Aleksander S.

    2014-01-01

    Induction of tumor angiogenesis is among the hallmarks of cancer and a driver of metastatic cascade initiation. Recent advances in high-resolution imaging enable highly detailed three-dimensional geometrical representation of the whole-tumor microvascular architecture. This enormous increase in complexity of image-based data necessitates the application of informatics methods for the analysis, mining and reconstruction of these spatial graph data structures. We present a novel methodology that combines ex-vivo high-resolution micro-computed tomography imaging data with a bioimage informatics algorithm to track and reconstruct the whole-tumor vasculature of a human breast cancer model. The reconstructed tumor vascular network is used as an input of a computational model that estimates blood flow in each segment of the tumor microvascular network. This formulation involves a well-established biophysical model and an optimization algorithm that ensures mass balance and detailed monitoring of all the vessels that feed and drain blood from the tumor microvascular network. Perfusion maps for the whole-tumor microvascular network are computed. Morphological and hemodynamic indices from different regions are compared to infer their role in overall tumor perfusion. PMID:24342178

  7. SIAH2 protein expression in breast cancer is inversely related with ER status and outcome to tamoxifen therapy

    PubMed Central

    van der Willik, Kimberly D; Timmermans, Mieke M; van Deurzen, Carolien HM; Look, Maxime P; Reijm, Esther A; van Zundert, Wendy JHP; Foekens, Renée; Trapman-Jansen, Anita MAC; den Bakker, Michael A; Westenend, Pieter J; Martens, John WM; Berns, Els MJJ; Jansen, Maurice PHM

    2016-01-01

    Our previous study demonstrated that high mRNA levels for Seven in Absentia Homolog 2 (SIAH2) correlated with high Estrogen Receptor (ER) mRNA levels and with longer progression-free survival (PFS) after first-line tamoxifen. Others showed high SIAH2 protein levels in ER-negative breast cancer associated with an unfavorable relapse-free survival. In the current study, we investigated SIAH2 protein expression to clarify the discrepancy between protein and mRNA findings and to determine its diagnostic value in breast cancer patients. Tissue microarrays (TMAs) containing core specimens of primary breast tumors were immunohistochemically stained for SIAH2 protein. The TMAs analyzed a cohort of 746 patients with primary breast cancer (PBC) and a cohort of 245 patients with ER-positive metastatic breast cancer (MBC) treated with first-line tamoxifen. SIAH2 staining was scored for intensity and proportion of positive tumor cells and evaluated for its relationship with metastasis-free survival (MFS) and PFS. Multivariate survival analyses included traditional prognostic or predictive factors, respectively. The PBC-cohort had 263 patients with high SIAH2 protein expression and decreased expression of ER protein and mRNA levels (P = 0.005 and P = 0.003, respectively). High SIAH2 levels correlated with significant unfavorable MFS in lymph node negative, ER-positive breast cancer patients. The MBC-cohort had 86 patients with increased SIAH2 protein expression. High SIAH2 expression was associated with an unfavorable PFS after first-line tamoxifen in multivariate analyses (HR = 1.45; 95% CI, 1.07-1.96; P = 0.015). In conclusion, SIAH2 protein expression is especially observed in ER-negative tumors. Its prognostic value in breast cancer does not add to current prognostic markers. The proportion of SIAH2-positive cells can be used as biomarker to predict tamoxifen treatment failure in MBC patients. PMID:27186402

  8. A Rare Case of Breast Malignant Phyllodes Tumor With Metastases to the Kidney: Case Report.

    PubMed

    Karczmarek-Borowska, Bożenna; Bukala, Agnieszka; Syrek-Kaplita, Karolina; Ksiazek, Mariusz; Filipowska, Justyna; Gradalska-Lampart, Monika

    2015-08-01

    Phyllodes tumors are rare breast neoplasms. Surgery is the treatment of choice. The role of postoperative radiotherapy and chemotherapy is still under dispute, as there are no equivocal prognostic factors. Treatment failure results in the occurrence of distant metastasis-mainly to the lungs, bones, liver, and brain. We have described the case of a woman with a malignant phyllodes tumor of the breast that was surgically treated. She did not receive adjuvant therapy because there is no consensus on the role of postoperative chemotherapy and radiotherapy. One year following the surgery, the patient had left-sided nephrectomy performed because of a rapidly growing tumor of the kidney. Renal cancer was suspected; however, a histopathological examination revealed that it was a metastatic phyllodes tumor. At the same time, the patient was diagnosed as having metastases in the other kidney, the lungs, liver, and bones.Our case report describes not only an unusual localization of the metastases (in the kidneys), but also failure of the chemotherapy and the aggressive course of malignant phyllodes tumor. Identification of patients with high risk for distant metastasis and the introduction of uniform rules for the management of adjuvant chemotherapy and radiotherapy would make planning treatment as efficacious as possible. PMID:26287414

  9. The current use and attitudes towards tumor genome sequencing in breast cancer

    PubMed Central

    Gingras, I.; Sonnenblick, A.; de Azambuja, E.; Paesmans, M.; Delaloge, S.; Aftimos, Philippe; Piccart, M. J.; Sotiriou, C.; Ignatiadis, M.; Azim, H. A.

    2016-01-01

    There is increasing availability of technologies that can interrogate the genomic landscape of an individual tumor; however, their impact on daily practice remains uncertain. We conducted a 28-item survey to investigate the current attitudes towards the integration of tumor genome sequencing in breast cancer management. A link to the survey was communicated via newsletters of several oncological societies, and dedicated mailing by academic research groups. Multivariable logistic regression modeling was carried out to determine the relationship between predictors and outcomes. 215 physicians participated to the survey. The majority were medical oncologists (88%), practicing in Europe (70%) and working in academic institutions (66%). Tumor genome sequencing was requested by 82 participants (38%), of whom 21% reported low confidence in their genomic knowledge, and 56% considered tumor genome sequencing to be poorly accessible. In multivariable analysis, having time allocated to research (OR 3.37, 95% CI 1.84–6.15, p < 0.0001), working in Asia (OR 5.76, 95% CI 1.57 – 21.15, p = 0.01) and having institutional guidelines for molecular sequencing (OR 2.09, 95% 0.99–4.42, p = 0.05) were associated with a higher probability of use. In conclusion, our survey indicates that tumor genome sequencing is sometimes used, albeit not widely, in guiding management of breast cancer patients. PMID:26931736

  10. Surgical Management of Benign and Borderline Phyllodes Tumors of the Breast.

    PubMed

    Moutte, Amandine; Chopin, Nicolas; Faure, Christelle; Beurrier, Frédéric; Ho Quoc, Christophe; Guinaudeau, Florence; Treilleux, Isabelle; Carrabin, Nicolas

    2016-09-01

    Phyllodes tumors (PT) are uncommon fibroepithelial breast neoplasms and there is currently no clear consensual treatment for these tumors. The aim of our study was to evaluate the surgical management and outcome of benign and borderline PT. We retrospectively assessed 76 cases of benign or borderline PT managed at the Leon Berard comprehensive cancer center in Lyon, France between July 2003 and December 2013. The mean age at diagnosis was 37.9 years and the median follow-up was 58 months. Seventy-five patients (99%), with a mean tumor size of 27 mm, underwent a breast-conserving procedure. The tumor margins were considered positive (when the tumor was present at the inked surgical section) in seven of 76 cases (9%) and negative in 65 out of 76 cases (86%). We observed the presence of small negative surgical margins <10 mm in 89% and <1 mm in 71% of the patients. Although no re-excision was performed to increase these margins, we did not see any increase in the local recurrence rate (4%) when compared to recurrence rates reported in the literature. We thus suggest that systematic revision surgery for close or positive surgical margins for benign PT should not be systematically performed. However, as recurrences occur within 2 years of initial excision, we recommend a regular clinical and imaging follow-up especially during this period for which patient's compliance is essential. PMID:27265474

  11. A Rare Case of Breast Malignant Phyllodes Tumor With Metastases to the Kidney

    PubMed Central

    Karczmarek-Borowska, Bożenna; Bukala, Agnieszka; Syrek-Kaplita, Karolina; Ksiazek, Mariusz; Filipowska, Justyna; Gradalska-Lampart, Monika

    2015-01-01

    Abstract Phyllodes tumors are rare breast neoplasms. Surgery is the treatment of choice. The role of postoperative radiotherapy and chemotherapy is still under dispute, as there are no equivocal prognostic factors. Treatment failure results in the occurrence of distant metastasis—mainly to the lungs, bones, liver, and brain. We have described the case of a woman with a malignant phyllodes tumor of the breast that was surgically treated. She did not receive adjuvant therapy because there is no consensus on the role of postoperative chemotherapy and radiotherapy. One year following the surgery, the patient had left-sided nephrectomy performed because of a rapidly growing tumor of the kidney. Renal cancer was suspected; however, a histopathological examination revealed that it was a metastatic phyllodes tumor. At the same time, the patient was diagnosed as having metastases in the other kidney, the lungs, liver, and bones. Our case report describes not only an unusual localization of the metastases (in the kidneys), but also failure of the chemotherapy and the aggressive course of malignant phyllodes tumor. Identification of patients with high risk for distant metastasis and the introduction of uniform rules for the management of adjuvant chemotherapy and radiotherapy would make planning treatment as efficacious as possible. PMID:26287414

  12. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy

    PubMed Central

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  13. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.

    PubMed

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  14. Dual functions of autophagy in the response of breast tumor cells to radiation

    PubMed Central

    Bristol, Molly L.; Di, Xu; Beckman, Matthew J.; Wilson, Eden N.; Henderson, Scott C.; Maiti, Aparna; Fan, Zhen; Gewirtz, David A.

    2012-01-01

    In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D3 with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D3). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy. PMID:22498493

  15. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.

    PubMed

    Enriquez-Navas, Pedro M; Kam, Yoonseok; Das, Tuhin; Hassan, Sabrina; Silva, Ariosto; Foroutan, Parastou; Ruiz, Epifanio; Martinez, Gary; Minton, Susan; Gillies, Robert J; Gatenby, Robert A

    2016-02-24

    Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors-an evolutionary phenomenon termed "competitive release." We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor-positive (ER(+)) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer. PMID:26912903

  16. How to Boost the Breast Tumor Bed? A Multidisciplinary Approach in Eight Steps

    SciTech Connect

    Kirova, Youlia M. Fournier-Bidoz, Nathalie; Servois, Vincent; Laki, Fatima; Pollet, Guillaume A.; Salmon, Remy; Thomas, Alexandra; Dendale, Remi; Bollet, Marc A.; Campana, Francois M.D.; Fourquet, Alain

    2008-10-01

    Purpose: To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. Patients and Methods: This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. Results: Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5-10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. Conclusions: We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

  17. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer

    PubMed Central

    Enriquez-Navas, Pedro M.; Kam, Yoonseok; Das, Tuhin; Hassan, Sabrina; Silva, Ariosto; Foroutan, Parastou; Ruiz, Epifanio; Martinez, Gary; Minton, Susan; Gillies, Robert J.; Gatenby, Robert A.

    2016-01-01

    Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors—an evolutionary phenomenon termed “competitive release.” We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor–positive (ER+) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer. PMID:26912903

  18. Tumor-Associated Macrophage-Mediated Targeted Therapy of Triple-Negative Breast Cancer.

    PubMed

    Niu, Mengmeng; Valdes, Solange; Naguib, Youssef W; Hursting, Stephen D; Cui, Zhengrong

    2016-06-01

    Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. TNBC is often infiltrated with a large number of macrophages, which in turn promote tumor growth and metastasis. In this study, tumor-associated macrophages (TAMs) were exploited as a target to deliver doxorubicin (DOX), a chemotherapeutic agent, to TNBC using nanoparticles surface-functionalized by (i) acid-sensitive sheddable PEGylation and (ii) modifying with mannose (i.e., DOX-AS-M-PLGA-NPs). In mice with orthotopic M-Wnt triple-negative mammary tumors, a single intravenous injection of DOX-AS-M-PLGA-NPs significantly reduced macrophage population in tumors within 2 days, and the density of the macrophages recovered slowly. Repeated injections of DOX-AS-M-PLGA-NPs can help maintain the population of the macrophages at a lower level. In M-Wnt tumor-bearing mice that were pretreated with zoledronic acid to nonselectively deplete macrophages, the TAM-targeting DOX-AS-M-PLGA-NPs were not more effective than the DOX-AS-PLGA-NPs that were not surface-modified with mannose and thus do not target TAMs in controlling tumor growth. However, in M-Wnt tumor-bearing mice that were not pretreated with zoledronic acid, the TAM-targeting DOX-AS-M-PLGA-NPs were significantly more effective than the nontargeting DOX-AS-PLGA-NPs in controlling the tumor growth. The AS-M-PLGA-NPs or other nanoparticles surface-functionalized similarly, when loaded with a chemotherapeutic agent commonly used in adjuvant therapy of TNBC, may be developed into targeted therapy for TNBC. PMID:27074028

  19. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    PubMed Central

    Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim

    2016-01-01

    Background Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID:27499638

  20. Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors

    NASA Astrophysics Data System (ADS)

    Chandler, E. M.; Saunders, M. P.; Yoon, C. J.; Gourdon, D.; Fischbach, C.

    2011-02-01

    Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-β serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose-derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies.

  1. Peutz-Jeghers Syndrome with Multiple Genital Tract Tumors and Breast Cancer: A Case Report with a Review of Literatures

    PubMed Central

    Song, Seung-Hun; Lee, Jae-Kwan; Saw, Ho-Suk; Choi, Sang-Yong; Koo, Bum-Hwan; Kim, Aeree; Yeom, Bum-Woo

    2006-01-01

    We report here on the multiple genital tract neoplasms in a 41-yr-old Korean woman with Peutz-Jeghers Syndrome (PJS). The patient presented with lower abdominal pain. Her previous medical history was PJS and breast cancer. Pelvic ultrasound showed a multilocular cyst at the right adnexal region, diagnosed as bilateral ovarian mucinous borderline tumors. An ovarian sex cord tumor with annular tubules was incidentally diagnosed together with a minimal deviation adenocarcinoma of the uterine cervix and mucinous metaplasia of both the Fallopian tubal mucosa and the endometrium. Although the cases of multiple genital tract tumors with PJS has rarely been reported, the present case appears to be the first in Korea in which the PJS syndrome was complicated by multiple genital tract tumors and infiltrating carcinoma of the breast. The clinical significance of the multiple genital tract tumors and breast cancer associated with PJS is reviewed. PMID:16891826

  2. Peutz-Jeghers Syndrome with multiple genital tract tumors and breast cancer: a case report with a review of literatures.

    PubMed

    Song, Seung-Hun; Lee, Jae-Kwan; Saw, Ho-Suk; Choi, Sang-Yong; Koo, Bum-Hwan; Kim, Aeree; Yeom, Bum-Woo; Kim, Insun

    2006-08-01

    We report here on the multiple genital tract neoplasms in a 41-yr-old Korean woman with Peutz-Jeghers Syndrome (PJS). The patient presented with lower abdominal pain. Her previous medical history was PJS and breast cancer. Pelvic ultrasound showed a multilocular cyst at the right adnexal region, diagnosed as bilateral ovarian mucinous borderline tumors. An ovarian sex cord tumor with annular tubules was incidentally diagnosed together with a minimal deviation adenocarcinoma of the uterine cervix and mucinous metaplasia of both the Fallopian tubal mucosa and the endometrium. Although the cases of multiple genital tract tumors with PJS has rarely been reported, the present case appears to be the first in Korea in which the PJS syndrome was complicated by multiple genital tract tumors and infiltrating carcinoma of the breast. The clinical significance of the multiple genital tract tumors and breast cancer associated with PJS is reviewed. PMID:16891826

  3. Autoantibodies to tailor-made panels of tumor-associated antigens in breast carcinoma.

    PubMed

    Piura, Ettie; Piura, Benjamin

    2011-01-01

    Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the sera of cancer patients. In a previous review published in this journal, we have focused on recent knowledge related to circulating AAbs to individual TAAs in breast carcinoma. This review will focus on recent knowledge related to AAb assays to tailor-made panels of TAAs in breast carcinoma. So far, AAb assays to the following tailor-made panels of TAAs have been assessed in breast carcinoma: (1) p53, c-myc, HER2, NY-ESO-1, BRCA2, and MUC1, (2) IMP1, p62, Koc, p53, c-MYC, cyclin B1, and survivin, (3) PPIA, PRDX2, FKBP52, HSP-60, and MUC1, (4) MUC1, HER2, p53, and IGFBP2, (5) p53, HER2, IGFBP-2, and TOPO2α, (6) survivin and livin, (7) ASB-9, SERAC1, and RELT, and (8) p16, p53, and c-myc. Assessment of serum AAbs to a tailor-made panel of TAAs provides better sensitivity to diagnosis of breast carcinoma than measuring serum AAbs to a single TAA. Nevertheless, measurement of serum AAbs to a panel of TAAs for screening and early diagnosis of breast carcinoma is still investigational and should be carried out along with traditional diagnostic studies. PMID:21423545

  4. Breast cancer--new aspects of tumor biology: are calcitriol and cyclooxygenase-2 possible targets for breast cancer?

    PubMed

    Thill, M; Terjung, A; Friedrich, M

    2014-01-01

    Up until now there have been many advances in treatment options for breast cancers such as targeted therapies like monoclonal antibodies, tyrosine kinase inhibitors, mTOR antagonists, and vaccines. Despite these advances, there are still many more that warrant further exploration. Two of these targets might be the cyclooxygenase-2 (COX-2), the key enzyme required to convert arachidonic acid to prostaglandins, and calcitriol [1,25(OH)2D3] which is the biologically active form of vitamin D. Both calcitriol and the inhibition of COX-2 have shown antiproliferative and prodifferentiation, as well as pro-apoptotic effects in different malignancies in vitro and in vivo, and the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is known to have tumor suppressor activity. Furthermore, the combination ofcalcitriol and nonsteroidal anti-inflammatory drugs (NSAIDs), such as non-selective and selective COX-2 inhibitors, acting synergistically to achieve significant cell growth inhibition in prostate cancer. Some epidemiological studies suggest that vitamin D confers a moderate benefit against breast cancer while most epidemiological studies presume that NSAIDs confer the same. Nevertheless there is growing body of evidence that COX-2 expression is a fundamental step in breast cancer carcinogenesis. To date, clinical trials have been conducted in patients with different malignancies using treatment strategies including COX-2 inhibitors and calcitriol and are showing partially encouraging results. The goal of this review is to shed light on the association between the prostaglandin as well as vitamin D metabolism relating to the incidence and therapy of breast cancers. Moreover, this review will also highlight potential treatment options, as well as extract any existing interactions between the two metabolisms. PMID:25118473

  5. p53 alteration in morphologically normal/benign breast tissue in patients with triple-negative high-grade breast carcinomas: breast p53 signature?

    PubMed

    Wang, Xi; Stolla, Moritz; Ring, Brian Z; Yang, Qi; Laughlin, Todd S; Rothberg, Paul G; Skinner, Kristin; Hicks, David G

    2016-09-01

    p53 alterations have been identified in approximately 23% of breast carcinomas, particularly in hormone receptor-negative high-grade carcinomas. It is considered to be an early event in breast carcinogenesis. Nevertheless, the putative precursor lesion of high-grade breast carcinoma remains elusive. Breast excision specimens from 93 triple-negative high-grade invasive ductal carcinomas, 48 estrogen receptor (ER)-positive/progesterone receptor-positive/Her2-negative non-high-grade invasive ductal carcinomas, and 50 mammoplasty breasts were selected. At least 2 tissue blocks with tumor and adjacent benign tissue were sectioned and subjected to immunohistochemistry staining for p53. TP53 gene sequencing was performed on select tumors. Further immunohistochemistry staining for ER and Ki-67 was performed on consecutive sections of tissue with p53-positive normal/benign cells. Of the 93 high-grade carcinomas, 51 (55%) were positive for p53 alteration, whereas only 3 (6.25%) of the 48 non-high-grade carcinomas were p53 altered. Focal p53 positivity in adjacent normal/benign breast tissue was identified in 19 cases, and 18 of them also had p53 alteration in their carcinomas. Only 1 case had focal p53 staining in normal/benign tissue, but the tumor was negative for p53 alteration. No p53 staining positivity was identified in the mammoplasty specimens. The p53-stained normal/benign cells were ER negative and did not show an increase in the Ki-67 labeling index. These findings indicate that the p53 staining positivity in normal/benign breast tissue is not a random event. It could be considered as the "p53 signature" in breast and serve as an indicator for future potential risk of p53-positive high-grade breast carcinoma. PMID:27246177

  6. Preliminary study on the automated detection of breast tumors using the characteristic features from unenhanced MR images

    NASA Astrophysics Data System (ADS)

    Adachi, Hayato; Teramoto, Atsushi; Miyajo, Satomi; Yamamuro, Osamu; Ohmi, Kumiko; Nishio, Masami; Fujita, Hiroshi

    2015-03-01

    Breast cancer incidence tends to rise globally and the mortality rate for breast cancer is increasing in Japan. There are various screening modalities for breast cancer, and MRI examinations with high detection rate are used for high-risk groups, which are genetically prone to develop breast cancer. In the breast MRI examination, unenhanced T1 and T2 weighted images shows no significant difference in signal value between tumor and normal tissue. Therefore, tumors are identified with use of contrast enhanced kinetic curve obtained by dynamic scan using contrast agent. Some computer aided diagnosis methods using dynamic contrast enhanced MR images also have been proposed. However, contrast agent produces the allergic reaction in rare case; it should not be used for screening examinees. Here, MRI provides the anatomical and functional information by using various sequences without contrast agents. According to the reports, this information can discriminate between tumor and normal tissue. In this study, we analyzed unenhanced MR images by using plural sequences and developed an automated method for the detection of tumors. First, we extracted the breast region from the T1-weighted image semi-automatically. Next, using the threshold determined by considering the signal intensities of tumor and normal tissue, a thresholding method was applied for diffusion-weighted image to extract the first candidate regions. After labeling processing, the breast region removes outside candidates from Initial candidates. Then false positives are reduced by the rule-based classifier. Finally, we examined the remaining candidates as possible tumor regions. We applied the proposed method to 54 cases of MR images and evaluated its usefulness. As a result, the detection sensitivity was 71.9% and the abnormal regions were clearly detected. These results indicate that the proposed method may be useful for tumor detection in unenhanced breast MR images.

  7. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    SciTech Connect

    Yu, Wei; Chai, Hongyan; Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue; Yang, Guifang; Cai, Xiaojun; Falck, John R.; Yang, Jing

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  8. Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition.

    PubMed

    Maity, Gargi; De, Archana; Das, Amlan; Banerjee, Snigdha; Sarkar, Sandipto; Banerjee, Sushanta K

    2015-07-01

    Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis. PMID:25867761

  9. Breast Carcinomatous Tumoral Emboli Can Result From Encircling Lymphovasculogenesis Rather Than Lymphovascular Invasion

    PubMed Central

    Mahooti, Sepi; Porter, Kyle; Alpaugh, Mary L.; Ye, Yin; Xiao, Yi; Jones, Susie; Tellez, Joseph D.; Barsky, Sanford H.

    2010-01-01

    The canonical view of the origin of tumor lymphovascular emboli is that they usually originate from lymphovascular invasion as part of a multistep metastatic process. Recent experimental evidence has suggested that metastasis can occur earlier than previously thought and we found evidence that tumor emboli formation can result from the short-circuiting step of encircling lymphovasculogenesis. Experimentally, we used a xenograft of human inflammatory breast cancer (MARY-X), a model that exhibited florid tumor emboli, to generate tumoral spheroids in vitro. In observational studies, we chose human breast carcinoma cases where there appeared to be a possible transition of in situ carcinoma to lymphovascular emboli without intervening stromal invasion. These cases were studied by morphometry as well as IHC with tumor proliferation (Ki-67) and adhesion (E-cadherin) markers, myoepithelial (p63), as well as endothelial (podoplanin [D2-40], CD31, VEGFR-3, Prox-1) markers. Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels. In vitro studies demonstrated that the tumoral spheroids induced endothelial differentiation of cocultured myoepithelial cells and MEFs, measured by real time PCR and immunofluorescence. In humans, the in situ clusters exhibited similar proliferation, E-cadherin immunoreactivity and size as the tumor emboli (p =.5), suggesting the possibility that the latter originated from the former. The in situ clusters exhibited a loss (50%-100%) of p63 myoepithelial immunoreactivity but not E-cadherin epithelial immunoreactivity. The tumor emboli were mainly present within lymphatic channels whose dual p63/CD31, p63/D2-40 and p63/VEGFR-3 and overall weak patterns of D2-40/CD31/VEGFR-3 immunoreactivities suggested that they represented immature and newly created

  10. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response.

    PubMed Central

    Heppner, K. J.; Matrisian, L. M.; Jensen, R. A.; Rodgers, W. H.

    1996-01-01

    Matrix metalloproteinase (MMP) family members have been associated with advanced-stage cancer and contribute to tumor progression, invasion, and metastasis as determined by inhibitor studies. In situ hybridization was performed to analyze the expression and localization of all known MMPs in a series of human breast cancer biopsy specimens. Most MMPs were localized to tumor stroma, and all MMPs had very distinct expression patterns. Matrilysin was expressed by morphologically normal epithelial ducts within tumors and in tissue from reduction mammoplasties, and by epithelial-derived tumor cells. Many family members, including stromelysin-3, gelatinase A, MT-MMP, interstitial collagenase, and stromelysin-1 were localized to fibroblasts of tumor stroma of invasive cancers but in quite distinct, and generally widespread, patterns. Gelatinase B, collagenase-3, and metalloelastase expression were more focal; gelatinase B was primarily localized to endothelial cells, collagenase-3 to isolated tumor cells, and metalloelastase to cytokeratin-negative, macrophage-like cells. The MMP inhibitor, TIMP-1, was expressed in both stromal and tumor components in most tumors, and neither stromelysin-2 nor neutrophil collagenase were detected in any of the tumors. These results indicate that there is very tight and complex regulation in the expression of MMP family members in breast cancer that generally represents a host response to the tumor and emphasize the need to further evaluate differential functions for MMP family members in breast tumor progression. Images Figure 1 Figure 2 Figure 3 PMID:8686751

  11. Diagnosis of breast tumor using thermal tomography q - r curve

    NASA Astrophysics Data System (ADS)

    Shi, Guilian; Wang, Lin; Han, Fei; Liang, Chengwen; Li, Kaiyang

    2015-06-01

    Metabolic heat, the product following the metabolism of cells, is closely related to the pathological information of living organisms, which means there are strong connections between the heat distribution and the pathological state of the living organism. The mathematical function δ is introduced in the classical Pennes bioheat transfer equation as a point heat source, and by simplifying the boundary condition, a bioheat transfer model is established. Based on the temperature distribution of the human body surface, the q-r curve of heat intensity q varying with depth r is acquired while combining the fitting method of the Lorentz curve. According to 34,977 clinical confirmed cases and the corresponding classified statistics, diagnostic criteria (for breast diseases) for judging diseases by the q-r curve are proposed. The P-value of our statistics is <0.05, which means our classified statistics are reliable. Six typical clinical examinations are performed, and the diagnosis results are very consistent with those of B-ultrasonic images, molybdenum target x-ray, and pathological examination, which suggests that the method of diagnosing diseases with a q-r curve has very good prospects for application. It is radiation free and noninvasive to the human body.

  12. Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

    PubMed

    Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

    2016-08-01

    Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. PMID:27196773

  13. Identifying metastatic breast tumors using textural kinetic features of a contrast based habitat in DCE-MRI

    NASA Astrophysics Data System (ADS)

    Chaudhury, Baishali; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Gatenby, Robert A.; Gillies, Robert J.; Drukteinis, Jennifer S.

    2015-03-01

    The ability to identify aggressive tumors from indolent tumors using quantitative analysis on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) would dramatically change the breast cancer treatment paradigm. With this prognostic information, patients with aggressive tumors that have the ability to spread to distant sites outside of the breast could be selected for more aggressive treatment and surveillance regimens. Conversely, patients with tumors that do not have the propensity to metastasize could be treated less aggressively, avoiding some of the morbidity associated with surgery, radiation and chemotherapy. We propose a computer aided detection framework to determine which breast cancers will metastasize to the loco-regional lymph nodes as well as which tumors will eventually go on to develop distant metastses using quantitative image analysis and radiomics. We defined a new contrast based tumor habitat and analyzed textural kinetic features from this habitat for classification purposes. The proposed tumor habitat, which we call combined-habitat, is derived from the intersection of two individual tumor sub-regions: one that exhibits rapid initial contrast uptake and the other that exhibits rapid delayed contrast washout. Hence the combined-habitat represents the tumor sub-region within which the pixels undergo both rapid initial uptake and rapid delayed washout. We analyzed a dataset of twenty-seven representative two dimensional (2D) images from volumetric DCE-MRI of breast tumors, for classification of tumors with no lymph nodes from tumors with positive number of axillary lymph nodes. For this classification an accuracy of 88.9% was achieved. Twenty of the twenty-seven patients were analyzed for classification of distant metastatic tumors from indolent cancers (tumors with no lymph nodes), for which the accuracy was 84.3%.

  14. Relationships between LDH-A, Lactate and Metastases in 4T1 Breast Tumors

    PubMed Central

    Rizwan, Asif; Serganova, Inna; Khanin, Raya; Karabeber, Hazem; Ni, Xiaohui; Thakur, Sunitha; Zakian, Kristen L.; Blasberg, Ronald; Koutcher, Jason A.

    2013-01-01

    Purpose To investigate the relationship between LDH-A expression, lactate concentration, cell metabolism and metastases in murine 4T1 breast tumors. Experimental Design Inhibition of LDH-A expression and protein levels were achieved in a metastatic breast cancer cell line (4T1) using shRNA technology. The relationship between tumor LDH-A protein levels and lactate concentration (measured by magnetic resonance spectroscopic imaging-MRSI) and metastases was assessed. Results LDH-A knockdown cells (KD9) showed a significant reduction in LDH-A protein and LDH activity, less acid production, decreased transwell migration and invasion, lower proliferation, reduced glucose utilization and glycolysis and increase in oxygen consumption, ROS and cellular ATP levels, compared to control (NC) cells cultured in 25 mM glucose. In vivo studies showed lower lactate levels in KD9, KD5, KD317 tumors than in NC or 4T1 wild-type tumors (p<0.01), and a linear relationship between tumor LDH-A protein expression and lactate concentration. Metastases were delayed and primary tumor growth rate decreased. Conclusions We show for the first time that LDH-A knockdown inhibited the formation of metastases, and was accompanied by in vivo changes in tumor cell metabolism. Lactate MRSI can be used as a surrogate to monitor targeted inhibition of LDH-A in a pre-clinical setting and provides a non-invasive imaging strategy to monitor LDH-A targeted therapy. This imaging strategy can be translated to the clinic to identify and monitor patients who are at high risk of developing metastatic disease. PMID:23833310

  15. Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

    PubMed Central

    Veiseh, Mandana; Kwon, Daniel H.; Borowsky, Alexander D.; Tolg, Cornelia; Leong, Hon S.; Lewis, John D.; Turley, Eva A.; Bissell, Mina J.

    2014-01-01

    Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA–HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10–480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA−/low vs. HAhigh) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA–binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HAhigh subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA−/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations. PMID:24733940

  16. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

    SciTech Connect

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  17. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters.

    PubMed

    Cheung, Kevin J; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D; Fairchild, Amanda N; Gorin, Michael A; Verdone, James E; Pienta, Kenneth J; Bader, Joel S; Ewald, Andrew J

    2016-02-16

    Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs. PMID:26831077

  18. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

    PubMed Central

    Cheung, Kevin J.; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D.; Fairchild, Amanda N.; Gorin, Michael A.; Verdone, James E.; Pienta, Kenneth J.; Bader, Joel S.; Ewald, Andrew J.

    2016-01-01

    Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14+ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14+ epithelial tumor cell clusters disseminate collectively to colonize distant organs. PMID:26831077

  19. Is breast conservative surgery a reasonable option in multifocal or multicentric tumors?

    PubMed Central

    Houvenaeghel, Gilles; Tallet, Agnès; Jalaguier-Coudray, Aurélie; Cohen, Monique; Bannier, Marie; Jauffret-Fara, Camille; Lambaudie, Eric

    2016-01-01

    The incidence of multifocal (MF) and multicentric (MC) carcinomas varies widely among clinical studies, depending on definitions and methods for pathological sampling. Magnetic resonance imaging is increasingly used because it can help identify additional and conventionally occult tumors with high sensitivity. However, false positive lesions might incorrectly influence treatment decisions. Therefore, preoperative biopsies must be performed to avoid unnecessary surgery. Most studies have shown higher lymph node involvement rates in MF/MC tumors than in unifocal tumors. However, the rate of local recurrences is usually low after breast conservative treatment (BCT) of MC/MF tumors. It has been suggested that BCT is a reasonable option for MC/MF tumors in women aged 50-69 years, with small tumors and absence of extensive ductal carcinoma in situ. A meta-analysis showed an apparent decreased overall survival in MC/MF tumors but data are controversial. Surgery should achieve both acceptable cosmetic results and negative margins, which requires thorough preoperative radiological workup and localization of lesions. Boost radiotherapy techniques must be evaluated since double boosts might result in increased toxicity, namely fibrosis. In conclusion, BCT is feasible in selected patients with MC/MF but the choice of surgery must be discussed in a multidisciplinary team comprising at least radiologists, surgeons and radiotherapists. PMID:27081646

  20. Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study

    NASA Astrophysics Data System (ADS)

    Priya, Mallika; Satish Rao, Bola Sadashiva; Chandra, Subhash; Datta, Anirbit; Nayak, Subramanya G.; Mahato, Krishna Kishore

    2015-10-01

    The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000 mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB® algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. T