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Sample records for er-positive breast tumors

  1. 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.

  2. Mice expressing myrAKT1 in the mammary gland develop carcinogen-induced ER-positive mammary tumors that mimic human breast cancer.

    PubMed

    Blanco-Aparicio, Carmen; Pérez-Gallego, Lucía; Pequeño, Belén; Leal, Juan F M; Renner, Oliver; Carnero, Amancio

    2007-03-01

    AKT1/PKB is a serine/threonine protein kinase that regulates biological processes such as proliferation, apoptosis and growth in a variety of cell types. To assess the oncogenic capability of an activated form of AKT in vivo we have generated several transgenic mouse lines that overexpress in the mammary epithelium the murine Akt1 gene modified with a myristoylation signal, which renders active this protein by localizing it to the plasma membrane. We demonstrate that expression of myristoylated AKT in the mammary glands increases the susceptibility of these mice to the induction of mammary tumors of epithelial origin by the carcinogen 9,10-dimethyl-1,2 benzanthracene (DMBA). We have found that while carcinogen-treated wild-type mice show mostly mammary tumors of sarcomatous origin, AKT transgenic mice treated with DMBA developed mainly adenocarcinoma or adenosquamous tumors, all of them displaying activated AKT. We analyzed other possible molecular alterations cooperating with AKT and found that neither Ras nor beta-catenin/Wnt pathways seemed altered nor p53 mutated. We have found that 100% of mammary DMBA-induced tumors and benign lesions in myrAKT mice are estrogen receptor (ERalpha)-positive and are more frequent than in wild-type littermates. These data show that AKT activation cooperates with deregulation of the estrogen receptor in the DMBA-induced mammary tumorigenesis model and recapitulate two characteristics of some human breast tumors. Thus, our model might provide a preclinical relevant model system to study the role of AKT and ERalpha in breast tumorigenesis and the response of mammary gland tumors to chemotherapeutics.

  3. Anti-miR-203 suppresses ER-positive breast cancer growth and stemness by targeting SOCS3

    PubMed Central

    Muhammad, Naoshad; Bhattacharya, Sourav; Steele, Robert; Ray, Ratna B.

    2016-01-01

    Breast cancer is a major public health problem worldwide in women and existing treatments are not adequately effective for this deadly disease. microRNAs (miRNAs) regulate the expression of many target genes and play pivotal roles in the development, as well as in the suppression of many cancers including breast cancer. We previously observed that miR-203 was highly upregulated in breast cancer tissues and in ER-positive breast cancer cell lines. In our present study, we observed that anti-miR-203 suppresses breast cancer cell proliferation in vitro. Orthotopic implantation of miR-203 depleted MCF-7 cells into nude mice displays smaller tumor growth as compared to control MCF-7 cells. Furthermore, miR-203 expression is significantly higher in ER-positive breast cancer patients as compared to ER-negative patients. We identified suppressor of cytokine signaling 3 (SOCS3) as a direct target of miR-203. Here we observed that miR-203 expression is inversely correlated with SOCS3 expression in ER-positive breast cancer samples. Additionally, we found that anti-miR-203 suppressed the expression of pStat3, pERK and c-Myc in MCF-7 and ZR-75-1 cells. We also demonstrated that anti-miR-203 decreased mammospheres formation and expression of stem cell markers in MCF-7 and ZR-75-1 cells. Taken together, our data suggest that anti-miR-203 has potential as a novel therapeutic strategy in ER-positive breast cancer treatment. PMID:27517632

  4. p53, a Target of Estrogen Receptor (ER) α, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells*

    PubMed Central

    Berger, Crystal E.; Qian, Yingjuan; Liu, Gang; Chen, Hongwu; Chen, Xinbin

    2012-01-01

    In response to genotoxic stress, the p53 tumor suppressor induces target genes for cell cycle arrest, apoptosis, and DNA repair. Although p53 is the most commonly mutated gene in all human cancers, it is only mutated in about 20% of breast cancers. 70% of all breast cancer cases are estrogen receptor (ER)-positive and express ERα. ER-positive breast cancer generally indicates good patient prognosis and treatment responsiveness with antiestrogens, such as tamoxifen. However, ER-positive breast cancer patients can experience loss or a reduction in ERα, which is associated with aggressive tumor growth, increased invasiveness, poor prognosis, and loss of p53 function. Consistent with this, we found that p53 is a target gene of ERα. Specifically, we found that knockdown of ERα decreases expression of p53 and its downstream targets, MDM2 and p21. In addition, we found that ERα activates p53 transcription via binding to estrogen response element half-sites within the p53 promoter. Moreover, we found that loss of ERα desensitizes, whereas ectopic expression of ERα sensitizes, breast cancer cells to DNA damage-induced growth suppression in a p53-dependent manner. Altogether, this study provides an insight into a feedback loop between ERα and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers. PMID:22787161

  5. The impact of cyclin D1 overexpression on the prognosis of ER-positive breast cancers: a meta-analysis.

    PubMed

    Xu, Xiao-Ling; Chen, Shu-Zheng; Chen, Wei; Zheng, Wei-Hui; Xia, Xiang-Hou; Yang, Hong-Jian; Li, Bo; Mao, Wei-Min

    2013-06-01

    Cyclin D1 (CCND1), a key regulator of cell cycle progression, is overexpressed in many human cancers, including breast cancer. However, the impact of CCND1 overexpression in these cancers remains unclear and controversial. We conducted a systematic literature search in PubMed and EMBASE with the search terms "cyclin D1", "CCND1", "breast cancer", "prognosis", and potential studies for analysis were selected. Studies with survival data, including progression-free survival (PFS), overall survival (OS) or metastasis-free survival (MFS), were included in this meta-analysis. A total of 33 studies containing 8,537 cases were included. The combined hazard risk (HR) and its 95 % confidence interval (CI) of OS, PFS and MFS were 1.13 (95 % CI 0.87-1.47; P = 0.35), 1.25 (95 % CI 0.95-1.64; P = 0.12), and 1.04 (95 % CI 0.80-1.36; P = 0.76), respectively, for primary breast cancer patients with tumors exhibiting CCND1 overexpression. Interestingly, the impact of CCND1 expression on OS was a 1.67-fold (95 % CI 1.38-2.02; P = 0.00) increased risk for ER-positive breast cancer patients. However, CCND1 overexpression exhibited no association with the PFS or OS of patients who received epirubicin-based neoadjuvant chemotherapy, for which the P values were 0.63 and 0.47, respectively. In summary, CCND1 overexpression impacts the prognosis of ER-positive breast cancer patients, but not patients with unselected primary breast cancer or patients treated with neoadjuvant chemotherapy.

  6. The role of S6K1 in ER-positive breast cancer.

    PubMed

    Holz, Marina K

    2012-09-01

    The 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target.

  7. Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen.

    PubMed

    Nyante, Sarah J; Sherman, Mark E; Pfeiffer, Ruth M; Berrington de Gonzalez, Amy; Brinton, Louise A; Bowles, Erin J Aiello; Hoover, Robert N; Glass, Andrew; Gierach, Gretchen L

    2016-01-01

    Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)-positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and ≤50 years (N = 6) or >50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and >50 years), tamoxifen duration (<4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction < 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines.

  8. Apoptosis/Necrosis Induction by Ultraviolet, in ER Positive and ER Negative Breast Cancer Cell Lines

    PubMed Central

    Shokrollahi Barough, Mahdieh; Hasanzadeh, Hadi; Barati, Mehdi; Pak, Fatemeh; Kokhaei, Parviz; Rezaei-Tavirani, Mostafa

    2015-01-01

    Background: Ultraviolet (UV) light exposure has been one of the major inducers of apoptosis. UV exposure has caused pyrimidine dimers and DNA fragmentation which might lead to cell cycle arrest and apoptosis signals activation. UV induced apoptosis has investigated in MDA-MB 468 as an ER negative breast adenocarcinoma and MCF-7 as an ER positive breast cancer cell line. Apoptosis induction rate by UV might be different in these two types of cells due to different biological characteristics of the cell. Objectives: In this paper we have evaluated serial dose of UV-B exposure on ER positive and ER negative breast cancer cell lines and its effect on apoptosis or necrosis induction in these cells. Materials and Methods: MDA-MB468 and MCF-7 cell lines have cultured for 24 hours and UV exposure has carried out at 290 nm at dose of 154 J/m2 to 18 KJ/m2 using UV lamp. UV exposed cells have incubated in cell culture condition for 24 or 48 hours following UV exposure and the cells have stained and analyzed by flow cytometry for apoptosis evaluation by Annexin V/PI method. Results: Apoptosis rate (PI and Annexin V double positive cells) after 24 hours incubation was higher in 24 hours in comparison with 48 hours incubation in both cell lines. The frequency of PI positive MDA-MB 468 cells was higher than PI and Annexin V double positive cells after 48 hours. PI positive MDA-MB 468 cells were significantly higher than MCF-7 cells in 24 hours incubation time. Conclusions: The results have shown that MDA-MB 468 cells were more sensitive to UV exposure and DNA fragmentation and necrosis pathway was dominant in these cells. PMID:26855725

  9. Apoptosis-, proliferation, immune function-, and drug resistance- related genes in ER positive, HER2 positive and triple negative breast cancer.

    PubMed

    Kolacinska, A; Chalubinska, J; Zawlik, I; Szymanska, B; Borowska-Garganisz, E; Nowik, M; Fendler, W; Kubiak, R; Pawlowska, Z; Morawiec, Z; Szemraj, J

    2012-01-01

    The aim of our study was to examine an association between gene expression assessed using a 23-gene microarray and receptor status of breast cancer samples categorized as ER positive, HER2 positive and triple negative subtypes. The ER positive cohort was subsequently divided into Luminal A, Luminal B HER2 negative and Luminal B HER2 positive subtypes. Core- needle biopsies were collected from 78 female patients with inoperable locally advanced breast cancer or resectable tumors suitable for downstaging, before any treatment. Expressions of 23 genes were determined by means of TagMan Low Density Arrays. Analysis of variance was used to select genes with discriminatory potential between receptor subtypes. We introduced a correction for false discovery rates (presented as q values) due to testing multiple hypothesis. Pairwise post-hoc comparisons of receptor subtypes were performed using Tukey 's HSD test. Five genes out of a 23-gene microarray differed significantly in relation to breast cancer receptor-based subtypes. Among these five genes, we identified: BCL2 (p=0.0002, q=0.0009), MKI67 (p=0.0037, q=0.0064), IGF1R (p=0.0040, q=0.0064), FOXC1 (p=0.0113, q=0.0135) and IRF1 (p=0.0435, q=0.0416) as ones showing ER positive, HER2 positive and triple negative -subtype specific expression profiles. When incorporating Luminal A, Luminal B HER2 negative, Luminal B HER2 positive subtypes into analysis, four genes: BCL2 (p=0.0006, q=0.0034), MKI67 (p=0.0078, q=0.0198), FOXC1 (p=0.0102, q=0.0198) and IGF1R (p=0.0174, q=0.0254) were selected. Elevated levels of IGF1R and BCL2 were significantly linked with Luminal A subtype. Triple negative breast cancer subtype was associated with higher expression of IRF1, FOXC1 and MKI67. In HER2 positive cohort lower expression of all five analyzed genes was noted.

  10. 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.

  11. A novel resveratrol-salinomycin combination sensitizes ER-positive breast cancer cells to apoptosis.

    PubMed

    Venkatadri, Rajkumar; Iyer, Anand Krishnan V; Kaushik, Vivek; Azad, Neelam

    2017-08-01

    Resveratrol is a dietary compound that has been widely reported for its anticancer activities. However, successful extrapolation of its effects to pre-clinical studies is met with limited success due to inadequate bioavailability. We investigated the potential of combination therapy to improve the efficacy of resveratrol in a more physiologically relevant dose range. The effect of resveratrol on canonical Wnt signaling was evaluated by Western blotting. Wnt modulators HLY78 (activator) and salinomycin (inhibitor) were evaluated in combination with resveratrol for their effect on breast cancer cell viability (MTT assay), cell cycle progression and apoptosis (Western blotting). Bliss independency model was used to evaluate combinatorial effects of resveratrol-salinomycin combination. Resveratrol downregulated canonical Wnt signaling proteins in treated breast cancer cells (MCF-7, MDA-MB-231 and MDA-MB-468) in the dose range of 50-200μM, which also affected cellular viability. However, at very low doses (0-50μM), resveratrol exhibited no cellular toxicity. Co-treatment with salinomycin significantly potentiated the anti-cancer effects of resveratrol, whereas HLY78 co-treatment had minimal effect. Bliss independency model revealed that Wnt inhibition synergistically potentiates the effects of resveratrol in MCF-7 and BT474 cells. Significantly downregulated canonical Wnt signaling proteins and marker of epithelial-mesenchymal transition (EMT), vimentin were observed in cells treated with resveratrol-salinomycin combination. Cell cycle arrest, caspase activation and apoptosis induction in cells treated with resveratrol-salinomycin combination further confirmed the efficacy of the combination. We report a novel resveratrol-salinomycin combination for targeting ER-positive breast cancer cells and present evidence for successful pre-clinical implementation of resveratrol. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban

  12. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer

    PubMed Central

    Law, Emily K.; Sieuwerts, Anieta M.; LaPara, Kelly; Leonard, Brandon; Starrett, Gabriel J.; Molan, Amy M.; Temiz, Nuri A.; Vogel, Rachel Isaksson; Meijer-van Gelder, Marion E.; Sweep, Fred C. G. J.; Span, Paul N.; Foekens, John A.; Martens, John W. M.; Yee, Douglas; Harris, Reuben S.

    2016-01-01

    Breast tumors often display extreme genetic heterogeneity characterized by hundreds of gross chromosomal aberrations and tens of thousands of somatic mutations. Tumor evolution is thought to be ongoing and driven by multiple mutagenic processes. A major outstanding question is whether primary tumors have preexisting mutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistance mutation preexists at the time of primary tumor presentation, then the intended therapy is likely to fail. However, if resistance does not preexist, then ongoing mutational processes still have the potential to undermine therapeutic efficacy. The antiviral enzyme APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B) preferentially deaminates DNA C-to-U, which results in signature C-to-T and C-to-G mutations commonly observed in breast tumors. We use clinical data and xenograft experiments to ask whether APOBEC3B contributes to ongoing breast tumor evolution and resistance to the selective estrogen receptor modulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor–positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment of metastatic ER+ disease. Second, APOBEC3B depletion in an ER+ breast cancer cell line results in prolonged tamoxifen responses in murine xenograft experiments. Third, APOBEC3B overexpression accelerates the development of tamoxifen resistance in murine xenograft experiments by a mechanism that requires the enzyme’s catalytic activity. These studies combine to indicate that APOBEC3B promotes drug resistance in breast cancer and that inhibiting APOBEC3B-dependent tumor evolvability may be an effective strategy to improve efficacies of targeted cancer therapies. PMID:27730215

  13. Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

    PubMed Central

    Aebi, S.; Sun, Z.; Braun, D.; Castiglione-Gertsch, M.; Rabaglio, M.; Gelber, R. D.; Crivellari, D.; Lindtner, J.; Snyder, R.; Karlsson, P.; Simoncini, E.; Gusterson, B. A.; Viale, G.; Regan, M. M.; Coates, A. S.; Goldhirsch, A.

    2011-01-01

    Background: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. Patients and methods: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. Results: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. Conclusion: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy. PMID:21282282

  14. Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.

    PubMed

    Prat, A; Parker, J S; Fan, C; Cheang, M C U; Miller, L D; Bergh, J; Chia, S K L; Bernard, P S; Nielsen, T O; Ellis, M J; Carey, L A; Perou, C M

    2012-11-01

    ER-positive (ER+) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only. Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan-Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance. All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%-100%). Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.

  15. NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer

    PubMed Central

    Xiong, Ying; Wang, Yan; Zheng, Junfang; Zhao, Yuan; Tao, Tao; Wang, Qiqi; Liu, Hua; Wang, Songlin; Jiang, Wen G.; He, Junqi

    2016-01-01

    G protein-coupled estrogen receptor (GPER) plays an important role in mediating the effects of estradiol. High levels of GPER have been implicated to associate with the malignant progress of invasive breast cancer (IBC). However, the mechanisms by which GPER protein levels were regulated remain unclear. In this study, PDZ protein Na+/H+ exchanger regulatory factor (NHERF1) was found to interact with GPER in breast cancer cells. This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. NHERF1 was demonstrated to facilitate GPER expression at post-transcriptional level and improve GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in a GPER/NHERF1 interaction-dependent manner. In addition, GPER protein levels are positively associated with NHERF1 protein levels in a panel of estrogen receptor (ER)-positive breast cancer cells. Furthermore, analysis of clinical IBC data from The Cancer Genome Atlas (TCGA) showed no significant difference in GPER mRNA levels between ER-positive IBC and normal breast tissues. However, gene set enrichment analysis (GSEA) showed that GPER signaling is ultra-activated in ER-positive IBC when compared with normal and its activation is positively associated with NHERF1 mRNA levels. Taken together, our findings identify NHERF1 as a new binding partner for GPER and its overexpression promotes protein stability and activation of GPER in ER-positive IBC. Our data indicate that regulation of GPER stability by NHERF1 may contribute to GPER-mediated carcinogenesis in ER-positive IBC. PMID:27448983

  16. NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer.

    PubMed

    Meng, Ran; Qin, Qiong; Xiong, Ying; Wang, Yan; Zheng, Junfang; Zhao, Yuan; Tao, Tao; Wang, Qiqi; Liu, Hua; Wang, Songlin; Jiang, Wen G; He, Junqi

    2016-08-23

    G protein-coupled estrogen receptor (GPER) plays an important role in mediating the effects of estradiol. High levels of GPER have been implicated to associate with the malignant progress of invasive breast cancer (IBC). However, the mechanisms by which GPER protein levels were regulated remain unclear. In this study, PDZ protein Na+/H+ exchanger regulatory factor (NHERF1) was found to interact with GPER in breast cancer cells. This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. NHERF1 was demonstrated to facilitate GPER expression at post-transcriptional level and improve GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in a GPER/NHERF1 interaction-dependent manner. In addition, GPER protein levels are positively associated with NHERF1 protein levels in a panel of estrogen receptor (ER)-positive breast cancer cells. Furthermore, analysis of clinical IBC data from The Cancer Genome Atlas (TCGA) showed no significant difference in GPER mRNA levels between ER-positive IBC and normal breast tissues. However, gene set enrichment analysis (GSEA) showed that GPER signaling is ultra-activated in ER-positive IBC when compared with normal and its activation is positively associated with NHERF1 mRNA levels. Taken together, our findings identify NHERF1 as a new binding partner for GPER and its overexpression promotes protein stability and activation of GPER in ER-positive IBC. Our data indicate that regulation of GPER stability by NHERF1 may contribute to GPER-mediated carcinogenesis in ER-positive IBC.

  17. Mixed Lineage Kinases as Novel Targets for the Treatment of Endocrine-Resistant, ER-Positive Breast Cancer

    DTIC Science & Technology

    2016-06-01

    AWARD NUMBER: W81XWH-15-1-0018 TITLE: Mixed-Lineage Kinases as Novel Targets for the Treatment of Endocrine-Resistant, ER-Positive Breast Cancer ...Positive Breast Cancer 5b. GRANT NUMBER W81XWH-15-1-0018 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Susan E. Conrad 5d. PROJECT NUMBER 5e. TASK NUMBER...the efficacy of this inhibitor in pre-clinical mouse xenograft models of human ER–positive breast cancer . During the current reporting period, we

  18. Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer.

    PubMed

    Bedard, Philippe L; Singhal, Sandeep K; Ignatiadis, Michail; Bradbury, Ian; Haibe-Kains, Benjamin; Desmedt, Christine; Loi, Sherene; Evans, Dean B; Michiels, Stefan; Dixon, J Michael; Miller, William R; Piccart, Martine J; Sotiriou, Christos

    2011-12-01

    The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10-14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10-14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.

  19. Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling.

    PubMed

    Dong, Liuyi; Yuan, Ye; Opansky, Cynthia; Chen, Yiliang; Aguilera-Barrantes, Irene; Wu, Shiyong; Yuan, Rong; Cao, Qi; Cheng, Yee Chung; Sahoo, Daisy; Silverstein, Roy L; Ren, Bin

    2017-04-04

    Obesity increases cancer risk including breast cancer (BC). However, the direct regulatory mechanisms by which obesity promotes BC progression remain largely unknown. We show that lysophosphatidic acid/protein kinase D1 (LPA/PKD-1)-CD36 signaling is a bona fide breast cancer promoter via stimulating microvascular remodeling in chronic diet-induced obesity (DIO). We observed that the growth of an estrogen receptor (ER) positive breast cancer was markedly increased when compared to the lean control, and specifically accompanied by increased microvascular remodeling in a syngeneic BC model in female DIO mice. The tumor neovessels in DIO mice demonstrated elevated levels of alpha smooth muscle actin (α-SMA), vascular endothelial growth factor receptor 2 (VEGFR 2) and endothelial differentiation gene 2/LPA receptor1 (Edg2/LPA1), enhanced PKD-1 phosphorylation, and reduced CD36 expression. Tumor associated endothelial cells (TAECs) exposed to LPA demonstrated sustained nuclear PKD-1 phosphorylation, and elevated mRNA levels of ephrin B2, and reduced mRNA expression of CD36. TAEC proliferation also increased in response to LPA/PKD-1 signaling. These studies suggest that the LPA/PKD-1-CD36 signaling axis links DIO to malignant progression of BC via stimulation of de novo tumor arteriogenesis through arteriolar remodeling of microvasculature in the tumor microenvironment. Targeting this signaling axis could provide an additional novel therapeutic strategy.

  20. The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer

    PubMed Central

    Yin, Yarong Diana; Fu, Melissa; Brooke, Darby G.; Heinrich, Daniel M.; Denny, William A.; Jamieson, Stephen M. F.

    2014-01-01

    AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required

  1. FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

    PubMed Central

    Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel; Hollingsworth, Emporia F.; Creighton, Chad J.; Li, Fugen; Shea, Martin; Nardone, Agostina; De Angelis, Carmine; Heiser, Laura M.; Anur, Pavana; Wang, Nicholas; Grasso, Catherine S.; Spellman, Paul T.; Tsimelzon, Anna; Gutierrez, Carolina; Huang, Shixia; Edwards, Dean P.; Trivedi, Meghana V.; Rimawi, Mothaffar F.; Lopez-Terrada, Dolores; Hilsenbeck, Susan G.; Gray, Joe W.; Brown, Myles; Osborne, C. Kent; Schiff, Rachel

    2016-01-01

    Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. PMID:27791031

  2. Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive Breast Cancer.

    PubMed

    Chimge, Nyam-Osor; Ahmed-Alnassar, Sara; Frenkel, Baruch

    2017-02-16

    RUNX1 plays opposing roles in breast cancer: a tumor suppressor in estrogen receptor-positive (ER(+)) disease and an oncogenic role in ER-negative (ER(-)) tumors. Potentially mediating the former, we have recently reported that RUNX1 prevents estrogen-driven suppression of the mRNA encoding the tumor suppressor AXIN1. Accordingly, AXIN1 protein expression was diminished upon RUNX1 silencing in ER(+) breast cancer cells and was positively correlated with AXIN1 protein expression across tumors with high levels of ER. Here we report the surprising observation that RUNX1 and AXIN1 proteins are strongly correlated in ER(-) tumors as well. However, this correlation is not attributable to regulation of AXIN1 by RUNX1 or vice versa. The unexpected correlation between RUNX1, playing an oncogenic role in ER(-) breast cancer, and AXIN1, a well-established tumor suppressor hub, may be related to a high ratio between the expression of variant 2 and variant 1 (v2/v1) of AXIN1 in ER(-) compared with ER(+) breast cancer. Although both isoforms are similarly regulated by RUNX1 in estrogen-stimulated ER(+) breast cancer cells, the higher v2/v1 ratio in ER(-) disease is expected to weaken the tumor suppressor activity of AXIN1 in these tumors.

  3. Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer.

    PubMed

    Patani, N; Martin, L-A

    2014-01-25

    Oestrogens (E) and oestrogen receptor alpha (ERα) play fundamental roles in the development and progression of more than three-quarters of breast cancers (BC). The ability to influence the natural history of BC by hormonal manipulation is well established and endocrine therapies represent the cornerstone of systemic management for women with ERα-positive disease. Endocrine agents abrogate oestrogenic signalling through distinct and incompletely overlapping mechanisms, either impeding the transcriptional activity of ERα or diminishing E-synthesis. In post-menopausal women, E-production is chiefly attributable to the enzymatic conversion of androgens in extra-gonadal tissues by the cytochrome P-450 superfamily member aromatase. Greater understanding of steroid biosynthesis has underpinned rational drug design and pharmacological development of potent and specific aromatase inhibitors (AIs). Contemporary agents induce profound E-suppression in post-menopausal women and are first-line neo-adjuvant, adjuvant and metastatic therapies, with greater efficacy and tolerability than tamoxifen. The principal qualifier for endocrine treatment, including AIs, remains ERα expression. However, it is increasingly apparent that ERα expression is not synonymous with sensitivity to treatment and insufficient to account for the considerable heterogeneity of response. Better predictive biomarkers of de novo resistance are required to improve patient selection and identify those poor-responders who may benefit from alternative or additional systemic treatment from the outset. Among patients who do respond well initially, many relapse during their clinical course and there is also an unmet need for biomarkers of acquired resistance. The majority of women who relapse on AIs continue to express functional ERα which remains a legitimate target for second-line endocrine therapy. Understanding and overcoming acquired resistance to AIs requires a greater appreciation of ERα biology and

  4. Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells.

    PubMed

    Wei, Yifang; Lai, Xiaofeng; Yu, Shentong; Chen, Suning; Ma, Yongzheng; Zhang, Yuan; Li, Huichen; Zhu, Xingmei; Yao, Libo; Zhang, Jian

    2014-09-01

    Recent studies have demonstrated that specific miRNAs, such as miR-221/222, may be responsible for tamoxifen resistance in breast cancer. Secreted miRNAs enclosed in exosomes can act as intercellular bio-messengers. Our objective is to investigate the role of secreted miR-221/222 in tamoxifen resistance of ER-positive breast cancer cells. Transmission electron microscopy analysis and nanoparticle tracking analysis were performed to determine the exosomes difference between MCF-7(TamR) (tamoxifen resistant) and MCF-7(wt) (tamoxifen sensitive) cells. PKH67 fluorescent labeling assay was used to detect exosomes derived from MCF-7(TamR) cells entering into MCF-7(wt) cells. The potential function of exosomes on tamoxifen resistance transmission was analyzed with cell viability, apoptosis ,and colony formation. MiRNA microarrays and qPCR were used to detect and compare the miRNAs expression levels in the two cells and exosomes. As the targets of miR-221/222, p27 and ERα were analyzed with western blot and qPCR. Compared with the MCF-7(wt) exosomes, there were significant differences in the concentration and size distribution of MCF-7(TamR) exosomes. MCF-7(wt) cells had an increased amount of exosomal RNA and proteins compared with MCF-7(TamR) cells. MCF-7(TamR) exosomes could enter into MCF-7(wt) cells, and then released miR-221/222. And the elevated miR-221/222 effectively reduced the target genes expression of P27 and ERα, which enhanced tamoxifen resistance in recipient cells. Our results are the first to show that secreted miR-221/222 serves as signaling molecules to mediate communication of tamoxifen resistance.

  5. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.

    PubMed

    Jansen, Valerie M; Bhola, Neil E; Bauer, Joshua A; Formisano, Luigi; Lee, Kyung-Min; Hutchinson, Katherine E; Witkiewicz, Agnieszka K; Moore, Preston D; Estrada, Mónica Valéria; Sánchez, Violeta; Ericsson, Paula G; Sanders, Melinda E; Pohlmann, Paula R; Pishvaian, Michael J; Riddle, David A; Dugger, Teresa C; Wei, Wenyi; Knudsen, Erik S; Arteaga, Carlos L

    2017-05-01

    Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors. Cancer Res; 77(9); 2488-99. ©2017 AACR. ©2017 American Association for Cancer Research.

  6. 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

  7. 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

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

    PubMed

    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

    Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50-65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER

  9. PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer.

    PubMed

    Kok, Marleen; Zwart, Wilbert; Holm, Caroline; Fles, Renske; Hauptmann, Michael; Van't Veer, Laura J; Wessels, Lodewyk F A; Neefjes, Jacques; Stål, Olle; Linn, Sabine C; Landberg, Göran; Michalides, Rob

    2011-01-01

    Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ERαS305-P (PKA/ERαS305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ERαS305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ERαS305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ERαS305-P (P = 0.037). Elevated PAK1 and PKA/ERαS305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ERαS305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

  10. Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts

    PubMed Central

    Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M.; Morandi, Andrea

    2016-01-01

    The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis. PMID:27602955

  11. Impact of Oncotype DX on treatment decisions in ER-positive, node-negative breast cancer with histologic correlation.

    PubMed

    Biroschak, Julianne R; Schwartz, Gordon F; Palazzo, Juan P; Toll, Adam D; Brill, Kristin L; Jaslow, Rebecca J; Lee, Sun Yong

    2013-01-01

    Oncotype DX, a gene-expression profiling assay, provides stratification of patients with estrogen-receptor positive, lymph-node-negative early breast cancer into risk groups based on recurrence score, which are associated with distant recurrence and response to chemotherapy. This study aims to determine whether Oncotype DX influences clinicians' treatment decisions, and whether assay results correlate with histologic assessment. Fifty patients with estrogen-receptor positive, node-negative early breast cancer analyzed by Oncotype DX and operated on by two breast surgeons were included. To assess effect on treatment decisions, clinical vignettes were created by retrospective chart review. Physicians were then presented with the clinical vignettes and instructed to make a treatment decisions (i.e., hormone therapy alone versus hormone therapy combined with chemotherapy) both before and after knowledge of the recurrence score. To assess correlation with histologic assessment, a prospective, blinded review of tumor slides was performed by two pathologists. Based on this review, tumors were placed into low, intermediate and high risk groups for comparison with Oncotype DX assay results. Treatment decisions were changed based on Oncotype DX results in 36 and 18% of cases by breast surgeons and medical oncologists, respectively. All tumors categorized as high risk by Oncotype DX were categorized as high risk based on histologic assessment, and 96% of cases categorized as low risk by recurrence score were categorized as low or intermediate risk by histologic assessment. Oncotype DX significantly influences management of estrogen-receptor positive, lymph-node-negative early breast cancer. Further studies are needed to assess association of histologic categorization to assay results. © 2013 Wiley Periodicals, Inc.

  12. Serum Metabolomic Profiles Identify ER-Positive Early Breast Cancer Patients at Increased Risk of Disease Recurrence in a Multicenter Population.

    PubMed

    Hart, Christopher D; Vignoli, Alessia; Tenori, Leonardo; Uy, Gemma Leonora; Van To, Ta; Adebamowo, Clement; Hossain, Syed Mozammel; Biganzoli, Laura; Risi, Emanuela; Love, Richard R; Luchinat, Claudio; Di Leo, Angelo

    2017-03-15

    Purpose: Detecting signals of micrometastatic disease in patients with early breast cancer (EBC) could improve risk stratification and allow better tailoring of adjuvant therapies. We previously showed that postoperative serum metabolomic profiles were predictive of relapse in a single-center cohort of estrogen receptor (ER)-negative EBC patients. Here, we investigated this further using preoperative serum samples from ER-positive, premenopausal women with EBC who were enrolled in an international phase III trial.Experimental Design: Proton nuclear magnetic resonance (NMR) spectroscopy of 590 EBC samples (319 with relapse or ≥6 years clinical follow-up) and 109 metastatic breast cancer (MBC) samples was performed. A Random Forest (RF) classification model was built using a training set of 85 EBC and all MBC samples. The model was then applied to a test set of 234 EBC samples, and a risk of recurrence score was generated on the basis of the likelihood of the sample being misclassified as metastatic.Results: In the training set, the RF model separated EBC from MBC with a discrimination accuracy of 84.9%. In the test set, the RF recurrence risk score correlated with relapse, with an AUC of 0.747 in ROC analysis. Accuracy was maximized at 71.3% (sensitivity, 70.8%; specificity, 71.4%). The model performed independently of age, tumor size, grade, HER2 status and nodal status, and also of Adjuvant! Online risk of relapse score.Conclusions: In a multicenter group of EBC patients, we developed a model based on preoperative serum metabolomic profiles that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors. Clin Cancer Res; 23(6); 1422-31. ©2017 AACR. ©2017 American Association for Cancer Research.

  13. 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.

  14. The prognostic significance of PELP1 expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype.

    PubMed

    Habashy, Hany Onsy; Powe, Desmond G; Rakha, Emad A; Ball, Graham; Macmillan, R Douglas; Green, Andrew R; Ellis, Ian O

    2010-04-01

    The transcription functions of oestrogen receptors (ER) are influenced by several coregulators such as PELP1 (proline, glutamate and leucine rich protein 1). The aim of the present study, which uses tissue microarrays and immunohistochemistry, is to explore the clinical and biological relevance of PELP1 protein expression in a large series of consecutive patients (1,162 patients) with invasive breast cancers with particular emphasis on its role in the ER-positive/luminal-like class of tumours. Our results showed that increased PELP1 expression is associated with tumours of larger size, higher histological grade, higher mitotic count, and with positive expression of basal cytokeratins (CK) (CK14; P = 0.018 and CK5/6; P = 0.029), P-cadherin (P = 0.002), p53 and MIB1 (P = 0.018). There was an inverse association between PELP1 expression and ER (P = 0.002), progesterone (PgR) (P = 0.004), androgen (AR) receptor (P < 0.001), and luminal CK (CK18; P = 0.027) expression. A significant association between PELP1 expression and shorter breast cancer specific survival (BCSS) (P = 0.002) and disease-free survival (DFI) (P = 0.006) was found. Multivariate Cox hazard analysis showed that PELP1 expression was an independent predictor of shorter BCSS (Hazard ratio (HR) = 1.349, P = 0.006) and shorter DFI (HR = 1.255, P = 0.011). In the ER-positive/luminal-like group (n = 768), PELP1 expression showed similar association with other clinicopathological variables and was an independent predictor of shorter DFI (HR = 1.256, P = 0.036). In conclusion, PELP1 protein expression is an independent prognostic predictor of shorter BCSS and DFI in breast cancer and its elevated expression is positively associated with markers of poor outcome. PELP1 appears to have a potential application in assessing the clinical outcome of patients with ER-positive breast cancer.

  15. Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer.

    PubMed

    Bhola, Neil E; 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; Allen, Eliezer V; Arteaga, Carlos L

    2015-01-15

    Estrogen receptor (ER) α-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 Ki-67 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. Pharmacologic 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 with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic 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. ©2014 American Association for Cancer Research.

  16. [Efficacy and Safety of the Selective Estrogen Receptor Down-Regulator "Fulvestrant" in Japanese Patients with Advanced, Recurrent, ER-Positive Postmenopausal Breast Cancer].

    PubMed

    Egawa, Chiyomi; Okishiro, Masatsugu; Takatsuka, Yuichi

    2015-07-01

    Fulvestrant is a novel endocrine therapy for breast cancer that exerts both anti-estrogenic and down-regulatory effects by binding to and degrading estrogen receptors (ERs). In the present study, the safety and effectiveness of 500 mg fulvestrant in 69 patients with advanced, recurrent, ER-positive postmenopausal breast cancer were investigated retrospectively. Outcomes were favorable for fulvestrant. The objective response rate was 24.6%, the clinical benefit rate was 49.2%, the median progression-free survival (PFS) was 203 days, and the median overall survival was 794 days. PFS tended to be longer in patients without a history of previous treatment or visceral metastasis. The main adverse events included injection site reactions and hot flushes; however, the majority of these events were mild to moderate. The present findings suggest that, among Japanese patients with advanced, recurrent, ER-positive postmenopausal breast cancer, 500 mg fulvestrant is effective and safe in those without metastasis and a minimal history of receipt of previous treatment regimens.

  17. Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer: a case control study.

    PubMed

    Kodahl, Annette R; Lyng, Maria B; Binder, Harald; Cold, Søren; Gravgaard, Karina; Knoop, Ann S; Ditzel, Henrik J

    2014-07-01

    There are currently no highly sensitive and specific minimally invasive biomarkers for detection of early-stage breast cancer. MicroRNAs (miRNAs) are present in the circulation and may be unique biomarkers for early diagnosis of human cancers. The aim of this study was to investigate the differential expression of miRNAs in the serum of breast cancer patients and healthy controls. Global miRNA analysis was performed on serum from 48 patients with ER-positive early-stage breast cancer obtained at diagnosis (24 lymph node-positive and 24 lymph node-negative) and 24 age-matched healthy controls using LNA-based quantitative real-time PCR (qRT-PCR). A signature of miRNAs was subsequently validated in an independent set of 111 serum samples from 60 patients with early-stage breast cancer and 51 healthy controls and further tested for reproducibility in 3 independent data sets from the GEO Database. A multivariable signature consisting of 9 miRNAs (miR-15a, miR-18a, miR-107, miR-133a, miR-139-5p, miR-143, miR-145, miR-365, miR-425) was identified that provided considerable discrimination between breast cancer patients and healthy controls. Further, the ability of the 9 miRNA signature to stratify samples from breast cancer patients and healthy controls was confirmed in the validation set (p = 0.012) with a corresponding AUC = 0.665 in the ROC-curve analysis. No association between miRNA expression and tumor grade, tumor size, menopausal- or lymph node status was observed. The signature was also successfully validated in a previously published independent data set of circulating miRNAs in early-stage breast cancer (p = 0.024). We present herein a 9 miRNA signature capable of discriminating between ER-positive breast cancer and healthy controls. Using a specific algorithm based on the 9 miRNA signature, the risk for future individuals can be predicted. Since microRNAs are highly stable in blood components, this signature might be useful in the development of a blood

  18. A Role for MEK-Interacting Protein 1 In Hormone Responsiveness of ER Positive Breast Cancer Cells

    DTIC Science & Technology

    2011-10-01

    migratory edge. Together, these data indicate that one function of MP1 in cell culture is related to spreading and migration. Studies performed in...which loss of ER expression is not the sole cause of cell death. Several studies indicate that ER may be implicated in breast cancer cell survival...were examined. Silencing of ER did not result in apoptosis of MCF-7 cells, indicating that decreased ER expr ession alone is not the cause of apoptosis

  19. EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer.

    PubMed

    Bertucci, François; Finetti, Pascal; Viens, Patrice; Birnbaum, Daniel

    2014-12-01

    The EndoPredict (EP) signature is a prognostic 11-gene expression signature specifically developed in ER+/HER2- node-negative/positive breast cancer. It is associated with relapse-free survival in patients treated with adjuvant hormone therapy, suggesting that EP low-risk patients could be treated with adjuvant hormone therapy alone whereas high-risk patients would deserve addition of adjuvant chemotherapy. Thus, it is important to determine whether EP high-risk patients are or are not more sensitive to chemotherapy than low-risk patients. Here, we have assessed the EP predictive value for pathological complete response to neoadjuvant chemotherapy in ER+/HER2- breast cancer. We gathered gene expression and histoclinical data of 553 pre-treatment ER+/HER2- breast carcinomas treated with anthracycline-based neoadjuvant chemotherapy. We searched for correlation between the pathological complete response (pCR) and the EP score-based classification. The overall pCR rate was 12%. Fifty-one percent of samples were classified as low-risk according to the EP score and 49% as high-risk. EP classification was associated with a pCR rate of 7% in the low-risk group and 17% in the high-risk group (p < 0.001). In multivariate analysis, the EP score remained significantly associated with pCR. Many genes upregulated in the high-risk tumours were involved in cell proliferation, whereas many genes upregulated in the low-risk tumours were involved in ER-signalling and stroma. Despite higher chemosensitivity, the high-risk group was associated with worse disease-free survival. In conclusion, EP high-risk ER+/HER2- breast cancers are more likely to respond to anthracycline-based chemotherapy.

  20. Increased expression of progesterone receptor membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and negative breast cancer.

    PubMed

    Ruan, Xiangyan; Zhang, Ying; Mueck, Alfred O; Willibald, Marina; Seeger, Harald; Fehm, Tanja; Brucker, Sara; Neubauer, Hans

    2017-02-01

    Expression of progesterone receptor membrane component 1 (PGRMC1) has been shown to be higher in breast cancer than normal tissue. We have previously shown that certain progestogens strongly stimulate proliferation of breast cancer cells overexpressing PGRMC1, and therefore hypothesize that PGRMC1 may play a critical role in breast cancer progression. Because little information is available if expression of PGRMC1 is also associated with worse prognosis for breast cancer patients, in this study we investigated the clinicopathologic significance of PGRMC1 expression in breast cancer tissue. Expression of PGRMC1 was analyzed by immunohistochemical staining of primary tumor tissues obtained from 69 breast cancer patients. A labeling score was developed, and results were correlated with tumor size, lymph node metastasis, and clinical outcome. Overexpression of PGRMC1 is correlating with larger tumor size and lymph node metastasis. Kaplan-Meier survival curves indicate that patients with PGRMC1 tumors have poorer disease-free and overall survival independent from the estrogen receptor status than breast cancer patients with PGRMC1 tumors. Our findings suggest that the expression of PGRMC1 might be useful for predicting prognosis in patients with breast cancer.

  1. Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer

    PubMed Central

    Rigter, L S; Loo, C E; Linn, S C; Sonke, G S; van Werkhoven, E; Lips, E H; Warnars, H A; Doll, P K; Bruining, A; Mandjes, I A; Vrancken Peeters, M J; Wesseling, J; Gilhuijs, K G; Rodenhuis, S

    2013-01-01

    Background: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with ‘luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. Methods: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a ‘favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an ‘unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. Results: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. Conclusion: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy. PMID:24149178

  2. Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer

    PubMed Central

    Cameron, D A; Camidge, D R; Oyee, J; Hirsch, M

    2008-01-01

    Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer. PMID:19018261

  3. Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer.

    PubMed

    Cameron, D A; Camidge, D R; Oyee, J; Hirsch, M

    2008-12-16

    Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of pound 301 359. This equated to pound 6500 per life years gained and pound 7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of pound 430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer.

  4. 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

  5. Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen.

    PubMed

    Snell, Cameron E; Gough, Madeline; Middleton, Kathryn; Hsieh, Michael; Furnas, Lauren; Seidl, Brenton; Gibbons, Kristen; Pyke, Christopher; Shannon, Catherine; Woodward, Natasha; Armes, Jane E

    2017-04-17

    Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (-) breast cancer could provide more accurate prognostic information. The retrospective cohort included 229 patients from a single institution with ER+, HER2- breast cancer who had synchronous ALN metastatic disease (2005-2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. One patient had an ER+ primary tumour, which was ER- in the ALN metastasis. 27 (11.3%) were PR- in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR- in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR- metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR- metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  6. The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.

    PubMed

    Bae, Woo Kyun; Yoo, Kyung Hyun; Lee, Ji Shin; Kim, Young; Chung, Ik-Joo; Park, Min Ho; Yoon, Jung Han; Furth, Priscilla A; Hennighausen, Lothar

    2015-10-01

    Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.

  7. Medico-economic impact of MSKCC non-sentinel node prediction nomogram for ER-positive HER2-negative breast cancers

    PubMed Central

    Guillot, Eugénie; Feron, Jean-Guillaume; Fourchotte, Virginie; Alran, Séverine; Pierga, Jean-Yves; Cottu, Paul; Lerebours, Florence; Stevens, Denise; Vincent-Salomon, Anne; Sigal-Zafrani, Brigitte; Campana, François; Rouzier, Roman; Reyal, Fabien

    2017-01-01

    Background Avoiding axillary lymph node dissection (ALND) for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB) could decrease morbidity with minimal clinical significance. Purpose The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN) prediction nomogram for ER+ HER2- breast cancer patients. Methods We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients’ characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results. Results A 0.3 threshold discriminate the type of sentinel node (SN) metastases: 98.8% of patients with pN0(i+) and 91.6% of patients with pN1(mic) had a MSKCC score under 0.3 (false negative rate = 6.4%). If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients. Conclusion We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+) or pN1(mic) ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3. PMID:28241044

  8. Pathobiology of the 129:Stat1 (-/-) mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype.

    PubMed

    Mori, Hidetoshi; Chen, Jane Q; Cardiff, Robert D; Pénzváltó, Zsófia; Hubbard, Neil E; Schuetter, Louis; Hovey, Russell C; Trott, Josephine F; Borowsky, Alexander D

    2017-09-02

    Stat1 gene-targeted knockout mice (129S6/SvEvTac-Stat1 (tm1Rds)) develop estrogen receptor-positive (ER(+)), luminal-type mammary carcinomas at an advanced age. There is evidence for both host environment as well as tumor cell-intrinsic mechanisms to initiate tumorigenesis in this model. In this report, we summarize details of the systemic and mammary pathology at preneoplastic and tumor-bearing time points. In addition, we investigate tumor progression in the 129:Stat1 (-/-) host compared with wild-type 129/SvEv, and we describe the immune cell reaction to the tumors. Mice housed and treated according to National Institutes of Health guidelines and Institutional Animal Care and Use Committee-approved methods were evaluated by histopathology, and their tissues were subjected to immunohistochemistry with computer-assisted quantitative image analysis. Tumor cell culture and conditioned media from cell culture were used to perform macrophage (RAW264.7) cell migration assays, including the 129:Stat1 (-/-)-derived SSM2 cells as well as control Met1 and NDL tumor cells and EpH4 normal cells. Tumorigenesis in 129:Stat1 (-/-) originates from a population of FoxA1(+) large oval pale cells that initially appear and accumulate along the mammary ducts in segments or regions of the gland prior to giving rise to mammary intraepithelial neoplasias. Progression to invasive carcinoma is accompanied by a marked local stromal and immune cell response composed predominantly of T cells and macrophages. In conditioned media experiments, cells derived from 129:Stat1 (-/-) tumors secrete both chemoattractant and chemoinhibitory factors, with greater attraction in the extracellular vesicular fraction and inhibition in the soluble fraction. The result appears to be recruitment of the immune reaction to the periphery of the tumor, with exclusion of immune cell infiltration into the tumor. 129:Stat1 (-/-) is a unique model for studying the critical origins and risk reduction strategies in age

  9. Comparison of risk classification between EndoPredict and MammaPrint in ER-positive/HER2-negative primary invasive breast cancer.

    PubMed

    Peláez-García, Alberto; Yébenes, Laura; Berjón, Alberto; Angulo, Antonia; Zamora, Pilar; Sánchez-Méndez, José Ignacio; Espinosa, Enrique; Redondo, Andrés; Heredia-Soto, Victoria; Mendiola, Marta; Feliú, Jaime; Hardisson, David

    2017-01-01

    To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas. Formalin-fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score). The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re-classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (κ = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (κ = 0.5, (95% CI, 0.232 to 0.768)). This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test.

  10. Comparison of risk classification between EndoPredict and MammaPrint in ER-positive/HER2-negative primary invasive breast cancer

    PubMed Central

    Peláez-García, Alberto; Yébenes, Laura; Berjón, Alberto; Angulo, Antonia; Zamora, Pilar; Sánchez-Méndez, José Ignacio; Espinosa, Enrique; Redondo, Andrés; Heredia-Soto, Victoria; Mendiola, Marta; Feliú, Jaime

    2017-01-01

    Purpose To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas. Methods Formalin-fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score). Results The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re-classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (κ = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (κ = 0.5, (95% CI, 0.232 to 0.768)). Conclusions This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test. PMID:28886093

  11. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation

    PubMed Central

    2013-01-01

    K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363. Treatment with IGFBP-3 blocked AZD5363-induced P-IGF-IR/InsR and T308 P-AKT, suggesting that receptor phosphorylation was dependent on increased autocrine ligands. Finally, treatment with the dual IGF-IR/InsR inhibitor AZD9362 enhanced the anti-tumor effect of AZD5363 in MCF-7/LTED cells and MCF-7 xenografts in ovariectomized mice devoid of estrogen supplementation. Conclusions These data suggest combinations of AKT and IGF-IR/InsR inhibitors would be an effective treatment strategy against hormone-independent ER+ breast cancer. PMID:23844554

  12. RERG (Ras-like, oestrogen-regulated, growth-inhibitor) expression in breast cancer: a marker of ER-positive luminal-like subtype.

    PubMed

    Habashy, Hany Onsy; Powe, Desmond G; Glaab, Enrico; Ball, Graham; Spiteri, Inmaculada; Krasnogor, Natalio; Garibaldi, Jonathan M; Rakha, Emad A; Green, Andrew R; Caldas, C; Ellis, Ian O

    2011-07-01

    Global gene expression profiling studies have classified breast cancer into a number of distinct biological and molecular classes with clinical relevance. The heterogeneous luminal group, which is largely characterised by oestrogen receptor (ER) expression, appears to contain distinct subgroups with differing behaviour. In this study, we analysed 47,293 gene transcripts in 128 invasive breast carcinomas (BC) using Artificial Neural Networks and a cross-validation analysis in combination with an ensemble sample classification to identify genes that can be used to subclassify ER+ luminal tumours. The results were validated using immunohistochemistry on TMAs containing 1,140 invasive breast cancers. Our results showed that the RERG gene is one of the highest ranked genes to differentiate between ER+ luminal-like and ER- non-luminal cancers based on a 10-fold external cross-validation analysis with an average classification accuracy of 89%. This was confirmed in our protein expression studies that showed RERG positive associations with markers of luminal differentiation including ER, luminal cytokeratins (CK19, CK18 and CK7/8) and FOXA1 (P = 0.004) and other markers of good prognosis in BC including small size, lower histologic grade and positive expression of androgen receptor, nuclear BRCA1, FHIT and cell cycle inhibitors p27 and p21. RERG expression was inversely associated with the proliferation marker MIB1 (P = 0.005) and p53. Strong RERG expression showed an association with longer breast cancer specific survival and distant metastasis free interval in the whole series as well as in the ER+ luminal group and these associations were independent of other prognostic variables. In conclusion, we used novel bioinformatics methods to identify candidate genes to characterise ER+ luminal-like breast cancer. RERG gene is a key marker of the luminal BC class and can be used to separate distinct prognostic subgroups.

  13. GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors.

    PubMed

    Morandi, Andrea; Martin, Lesley-Ann; Gao, Qiong; Pancholi, Sunil; Mackay, Alan; Robertson, David; Zvelebil, Marketa; Dowsett, Mitch; Plaza-Menacho, Ivan; Isacke, Clare M

    2013-06-15

    Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer.

  14. 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

  15. 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.

  16. Localization of tamoxifen in human breast cancer tumors by MALDI mass spectrometry imaging.

    PubMed

    Végvári, Ákos; Shavkunov, Alexander S; Fehniger, Thomas E; Grabau, Dorthe; Niméus, Emma; Marko-Varga, György

    2016-03-01

    Tamoxifen is used in endocrine treatment of breast cancer to inhibit estrogen signaling. A set of stratified ER-positive and ER-negative tumor sections was subjected to manual deposition of tamoxifen solution in order to investigate its spatial distribution upon exposure to interaction within thin tissue sections. The localization of tamoxifen in tumor sections was assessed by matrix assisted laser deposition/ionization mass spectrometry imaging. The images of extracted ion maps were analyzed for comparison of signal intensity distributions. The precursor ion of tamoxifen (m/z 372.233) displayed heterogeneous signal intensity distributions in histological compartments of tumor tissue sections. The levels of tamoxifen in tumor cells compared with stroma were higher in ER-positive tissues, whereas ER-negative tissue sections showed lower signal intensities in tumor cells. The experimental model was successfully applied on frozen tumor samples allowing for differentiation between ER groups based on distribution of tamoxifen.

  17. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

    PubMed

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

    2016-09-13

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

  18. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer

    PubMed Central

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D.; Verardo, Roberto; Leo, Angelo Di; Migliaccio, Ilenia

    2016-01-01

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 − 3.2] p = 1.87e−08 and HR = 2.62 [1.9− 3.5] p = 8.6e−11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted. PMID:27634906

  19. Diagnosis of breast tumors after breast reduction.

    PubMed

    Beer, G M; Kompatscher, P; Hergan, K

    1996-01-01

    We conducted a retrospective study to evaluate the diagnosability of breast tumors after breast reductions as this is a frequent surgical procedure. The data should shed light on the hypothesis that routine screening methods concerning the diagnosis of breast tumors prove more difficult after breast operations. All women who had undergone breast reduction at our department between January 1989 and December 1994 were examined. During this period we counted 166 patients; the majority of them (n = 144) had undergone a bilateral breast reduction and the rest of them (n = 22) a unilateral breast reduction for various reasons. After the operation, all patients were checked in standardized intervals. Those who developed any kind of breast mass (n = 6) were recorded and examined by ultrasound and mammography, and occasionally by an additional fine-needle biopsy. In case any doubt about the dignity had remained, an excisional biopsy was carried out. In none of our patients was it possible to get a precise diagnosis of an ill-defined mass with ultrasound. With mammography, some of the existing masses, which were really scars, mimicked different kinds of tumors, and once a carcinoma was initially interpreted as scar tissue with oil cysts. The diagnosis of breast masses after breast reductions with routinely used screening methods has proved to be more difficult as breast reductions lead to architectural alterations of the remaining breast parenchyma. Such alterations can and should be documented shortly after the operation so that later occurring tumors are distinguished more easily. Therefore, a basic mammography 3 months after each breast reduction has to be claimed in order to facilitate further breast tumor diagnosis.

  20. 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

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

    PubMed Central

    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.

    2015-01-01

    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, 2,552 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

  2. 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

  3. Distinct nuclear receptor expression in stroma adjacent to breast tumors.

    PubMed

    Knower, Kevin C; Chand, Ashwini L; Eriksson, Natalie; Takagi, Kiyoshi; Miki, Yasuhiro; Sasano, Hironobu; Visvader, Jane E; Lindeman, Geoffrey J; Funder, John W; Fuller, Peter J; Simpson, Evan R; Tilley, Wayne D; Leedman, Peter J; Graham, J Dinny; Muscat, George E O; Clarke, Christine L; Clyne, Colin D

    2013-11-01

    The interaction between breast tumor epithelial and stromal cells is vital for initial and recurrent tumor growth. While breast cancer-associated stromal cells provide a favorable environment for proliferation and metastasis, the molecular mechanisms contributing to this process are not fully understood. Nuclear receptors (NRs) are intracellular transcription factors that directly regulate gene expression. Little is known about the status of NRs in cancer-associated stroma. Nuclear Receptor Low-Density Taqman Arrays were used to compare the gene expression profiles of all 48 NR family members in a collection of primary cultured cancer-associated fibroblasts (CAFs) obtained from estrogen receptor (ER)α positive breast cancers (n = 9) and normal breast adipose fibroblasts (NAFs) (n = 7). Thirty-three of 48 NRs were expressed in both the groups, while 11 NRs were not detected in either. Three NRs (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1); estrogen-related receptor beta (ERR-β); and RAR-related orphan receptor beta (ROR-β)) were only detected in NAFs, while one NR (liver receptor homolog-1 (LRH-1)) was unique to CAFs. Of the NRs co-expressed, four were significantly down-regulated in CAFs compared with NAFs (RAR-related orphan receptor-α (ROR-α); Thyroid hormone receptor-β (TR-β); vitamin D receptor (VDR); and peroxisome proliferator-activated receptor-γ (PPAR-γ)). Quantitative immunohistochemistry for LRH-1, TR-β, and PPAR-γ proteins in stromal fibroblasts from an independent panel of breast cancers (ER-positive (n = 15), ER-negative (n = 15), normal (n = 14)) positively correlated with mRNA expression profiles. The differentially expressed NRs identified in tumor stroma are key mediators in aromatase regulation and subsequent estrogen production. Our findings reveal a distinct pattern of NR expression that therefore fits with a sustained and increased local estrogen microenvironment in ER-positive

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

    PubMed

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

    2014-03-01

    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. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  5. 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.

  6. Gene expression profiles of circulating tumor cells versus primary tumors in metastatic breast cancer.

    PubMed

    Onstenk, Wendy; Sieuwerts, Anieta M; Weekhout, Marleen; Mostert, Bianca; Reijm, Esther A; van Deurzen, Carolien H M; Bolt-de Vries, Joan B; Peeters, Dieter J; Hamberg, Paul; Seynaeve, Caroline; Jager, Agnes; de Jongh, Felix E; Smid, Marcel; Dirix, Luc Y; Kehrer, Diederik F S; van Galen, Anne; Ramirez-Moreno, Raquel; Kraan, Jaco; Van, Mai; Gratama, Jan W; Martens, John W M; Foekens, John A; Sleijfer, Stefan

    2015-06-28

    Before using circulating tumor cells (CTCs) as liquid biopsy, insight into molecular discrepancies between CTCs and primary tumors is essential. We characterized CellSearch-enriched CTCs from 62 metastatic breast cancer (MBC) patients with ≥5 CTCs starting first-line systemic treatment. Expression levels of 35 tumor-associated, CTC-specific genes, including ESR1, coding for the estrogen receptor (ER), were measured by reverse transcription quantitative polymerase chain reaction and correlated to corresponding primary tumors. In 30 patients (48%), gene expression profiles of 35 genes were discrepant between CTCs and the primary tumor, but this had no prognostic consequences. In 15 patients (24%), the expression of ER was discrepant. Patients with ER-negative primary tumors and ER-positive CTCs had a longer median TTS compared to those with concordantly ER-negative CTCs (8.5 versus 2.1 months, P = 0.05). From seven patients, an axillary lymph node metastasis was available. In two patients, the CTC profiles better resembled the lymph node metastasis than the primary tumor. Our findings suggest that molecular discordances between CTCs and primary tumors frequently occur, but that this bears no prognostic consequences. Alterations in ER-status between primary tumors and CTCs might have prognostic implications.

  7. Quantification of Estrogen Receptor Expression in Normal Breast Tissue in Postmenopausal Women With Breast Cancer and Association With Tumor Subtypes.

    PubMed

    Gulbahce, H Evin; Blair, Cindy K; Sweeney, Carol; Salama, Mohamed E

    2017-09-01

    Estrogen exposure is important in the pathogenesis of breast cancer and is a contributing risk factor. In this study we quantified estrogen receptor (ER) alpha expression in normal breast epithelium (NBR) in women with breast cancer and correlated it with breast cancer subtypes. Tissue microarrays were constructed from 204 breast cancer patients for whom normal breast tissue away from tumor was available. Slides stained with ER were scanned and expression in normal terminal duct lobular epithelium was quantitated using computer-assisted image analysis. ER expression in normal terminal duct lobular epithelium of postmenopausal women with breast cancer was significantly associated with estrogen and triple (estrogen, progesterone receptors, and HER2) negative phenotypes. Also increased age at diagnosis was significantly associated with ER expression in NBR. ER positivity in normal epithelium did not vary by tumor size, lymph node status, tumor grade, or stage. On the basis of quantitative image analysis, we confirm that ER expression in NBR increases with age in women with breast cancer, and report for the first time, a significant association between ER expression in NBR with ER-negative and triple-negative cancers in postmenopausal women.

  8. New Microscope Scans Breast Tumors During Surgery

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_166925.html New Microscope Scans Breast Tumors During Surgery The instrument ... 2017 WEDNESDAY, June 28, 2017 (HealthDay News) -- A new microscope could help surgeons remove breast tumors completely, ...

  9. 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

  10. Introducing Cichorium Pumilum as a potential therapeutical agent against drug-induced benign breast tumor in rats.

    PubMed

    Al-Akhras, M-Ali H; Aljarrah, Khaled; Al-Khateeb, Hasan; Jaradat, Adnan; Al-Omari, Abdelkarim; Al-Nasser, Amjad; Masadeh, Majed M; Amin, Amr; Hamza, Alaaeldin; Mohammed, Karima; Al Olama, Mohammad; Daoud, Sayel

    2012-12-01

    Cichorium Pumilum (chicory) is could be a promising cancer treatment in which a photosensitizing drug concentrates in benign tumor cells and activated by quanta at certain wavelength. Such activated extracts could lead to cell death and tumor ablation. Previous studies have shown that Cichorium Pumilum (chicory) contains photosensitive compounds such as cichoriin, anthocyanins, lactucin, and Lactucopicrin. In the present study, the protective effect of sun light-activated Cichorium against the dimethylbenz[a]anthracene (DMBA) induced benign breast tumors to female Sprague-Dawley rats was investigated. Chicory's extract has significantly increase P.carbonyl (PC) and malondialdehyde (MDA) and decreases the hepatic levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) in benign breast tumors-induced group compared to control. It also significantly decrease the number of estrogen receptors ER-positive cells in tumor masses. These results suggest that chicory extracts could be used as herbal photosensitizing agent in treating benign breast tumor in rats.

  11. Circulating Tumor Cells and Tumor Stem Cells Detection in the Peripheral Blood Mononuclear Cells of Breast Cancer.

    PubMed

    Wang, Feng; Li, Yuan-Chun; Liu, Li-Ping; Zhang, Hao-Min; Tong, Song

    2016-09-01

    Our aim was to retrospectively analyze the relationships between circulating tumor cells (CTCs) and the development of breast cancer, for elucidating the role of CTCs in breast cancer. A total of 107 female patients with primary breast cancer and 48 matched healthy female volunteers were recruited. After blood collection, isolation of peripheral blood mononuclear cells (PBMC) was performed followed by the detection of cytokeratin 19 positive (CK19(+) ) and CD44(+) /CD24(-/low) cells, as well as estrogen receptor (ER), progesterone, and CerbB2. Data were analyzed with the SPSS 20.0 software. None of the 48 volunteers were detected with CK19(+) cells in their PBMC, while in 77 patients, 72% of 107 female patients with primary breast cancer, the CK19(+) cells were detected. CK19(+) could also be detected among patients in each grouping by different clinical staging and lymph node metastasis, with statistical differences (all P < 0.05). Further, among the 83 CK19(+) specimens, 32 were also detected with CD44(+) /CD24(-/low) cells. Comparisons of CK19(+) and CD44(+) /CD24(-/low) cells in patients with different clinical features (ER positive vs. ER negative, C-erbB2 positive vs. C-erbB2 negative) and molecular subtypes (triple-negative breast cancer, ER positive, and C-erbB2 positive) showed no obvious difference (all P > 0.05). Both CTCs and tumor stem cells (TSCs) could be detected in the PBMC of breast cancer patients; besides, positive expression rate of CTCs might be obviously associated with the clinical stage and metastasis. Positive relationship of TSCs and the clinical stage of breast cancer was also proved in this study. © 2016 Wiley Periodicals, Inc.

  12. [Phyllodes breast tumors].

    PubMed

    Zedníková, I; Černá, M; Hlaváčková, M; Hes, O

    2015-01-01

    Phyllodes tumour is a breast tumour occurring very rarely. It accounts for only in 1% of all cases of breast tumour. The diagnosis of phyllodes tumours can be difficult in consideration of the small number of cases. Treatment of phyllodes tumours is always surgical. In 2004-2013, we operated on twelve female patients with phyllodes tumours out of the total number of 1564 surgeries for breast tumours (0.8%) at the Department of Surgery at Teaching Hospital in Pilsen. We evaluated the age, the biological behaviour of the tumour depending on the tumour size and duration, the distant metastases, therapy and survival. The average age at the time of surgery was fifty years (2684), the duration of disease to the surgical solution ranged from one month to ten years. Tumour size was in the range of two to twenty-nine centimetres, tumours measuring less than five centimetres were always benign. Tumour excision for benign phyllodes tumour was performed seven times. Malignant phyllodes tumour was diagnosed five times with mastectomy performed in each case, and the axilla was exenterated in three cases where nodes were benign in each of them. In one case, mastectomy was followed by radiotherapy because the tumour reached the edge of the resected part; the other patients were only monitored. In two patients, tumour spreading into the lungs was diagnosed at five to ten months after breast surgery. One patient with generalized disease died, the other ones live with no local recurrence of this disease. Median survival is fifty-two months; the disease-free interval is fifty months. The results show that if phyllodes tumour is diagnosed in time, it is almost exclusively benign. If the case history is longer and the tumour is growing, the likelihood of malignancy increases. Surgical treatment is also sufficient in the case of malignant forms. The breast surgery does not need to be supplemented with exenteration of axilla.Key words: breast - phyllodes tumour.

  13. Male breast cancer according to tumor subtype and race: a population-based study.

    PubMed

    Chavez-Macgregor, Mariana; Clarke, Christina A; Lichtensztajn, Daphne; Hortobagyi, Gabriel N; Giordano, Sharon H

    2013-05-01

    Breast cancer occurs rarely in men. To the authors' knowledge, no population-based estimates of the incidence of human epidermal growth factor receptor 2 (HER2)-positive breast cancer or of the distribution of breast cancer subtypes among male breast cancer patients have been published to date. Therefore, the objective of the current study was to explore breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California. This study included men who were diagnosed with invasive breast cancer between 2005 and 2009 with known estrogen receptor (ER) and progesterone receptor (PR) (together, hormone receptor [HR]) status and HER2 status reported to the California Cancer Registry. Among the men with HR-positive tumors, survival probabilities between groups were compared using log-rank tests. Six hundred six patients were included. The median age at diagnosis was 68 years. Four hundred ninety-four men (81.5%) had HR-positive tumors (defined as ER-positive and/or PR-positive and HER2-negative). Ninety men (14.9%) had HER2-positive tumors, and 22 (3.6%) had triple receptor-negative (TN) tumors. Among the patients with HR-positive tumors, non-Hispanic black men and Hispanic men were more likely to have PR-negative tumors than non-Hispanic white men. No statistically significant differences in survival were observed according to tumor subtype (P = .08). Differences in survival according to race/ethnicity were observed among all patients (P = .087) and among those with HR-positive tumors (P = .0170), and non-Hispanic black men had poorer outcomes. In this large, representative cohort of men with breast cancer, the distribution of tumor subtypes was different from that reported for women and varied by patient race/ethnicity. Non-Hispanic black men were more likely to have TN tumors and ER-positive/PR-negative tumors than white men. Copyright © 2013 American Cancer Society.

  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. BreastDefend enhances effect of tamoxifen in estrogen receptor-positive human breast cancer in vitro and in vivo.

    PubMed

    Cheng, Shujie; Castillo, Victor; Welty, Matt; Alvarado, Mark; Eliaz, Isaac; Temm, Constance J; Sandusky, George E; Sliva, Daniel

    2017-02-16

    Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. Here, we evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer. Cell proliferation and apoptosis were determined in ER-positive human breast cancer cells MCF-7 by MTT assay, quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP, respectively. The molecular mechanism was identified using RNA microarray analysis and western blotting. Tumor tissues from xenograft mouse model were analyzed by immunohistochemistry. Our data clearly demonstrate that a combination of 4-hydroxytamoxifen (4-OHT) with BD lead to profound inhibition of cell proliferation and induction of apoptosis in MCF-7 cells. This effect is consistent with the regulation of apoptotic and TAM resistant genes at the transcription and translation levels. Importantly, TAM and BD co-treatment significantly enhanced apoptosis, suppressed tumor growth and reduced tumor weight in a xenograft model of human ER-positive breast cancer. BD sensitized ER-positive human breast cancer cells to 4-OHT/TAM treatment in vitro and in vivo. BreastDefend can be used in an adjuvant therapy to increase the therapeutic effect of tamoxifen in patients with ER-positive breast cancer.

  16. Oxygenation-Enhanced Radiation Therapy of Breast Tumors

    DTIC Science & Technology

    2011-11-01

    10-1-0751 TITLE: Oxygenation-Enhanced Radiation Therapy of Breast Tumors PRINCIPAL INVESTIGATOR: Dr. Mikhail Skliar...locoregional breast cancer has evolved from radical mastectomy to targeted local therapy with breast conservation. The efficacy of conserving treatments...of breast cancers is impeded by tumor hypoxia, which affects 50% of locally advanced breast tumors. Poor oxygenation of hypoxic tumors reduces

  17. Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.

    PubMed

    Ambrosone, Christine B; Young, Allyson C; Sucheston, Lara E; Wang, Dan; Yan, Li; Liu, Song; Tang, Li; Hu, Qiang; Freudenheim, Jo L; Shields, Peter G; Morrison, Carl D; Demissie, Kitaw; Higgins, Michael J

    2014-01-15

    American women of African ancestry (AA) are more likely than European-Americans (EA) to be diagnosed with aggressive, estrogen receptor (ER) negative breast tumors; mechanisms underlying these disparities are poorly understood. We conducted a genome wide (450K loci) methylation analysis to determine if there were differences in DNA methylation patterns between tumors from AA and EA women and if these differences were similar for both ER positive and ER negative breast cancer. Methylation levels at CpG loci within CpG islands (CGI)s and CGI-shores were significantly higher in tumors (n=138) than in reduction mammoplasty samples (n=124). In hierarchical cluster analysis, there was separation between tumor and normal samples, and in tumors, there was delineation by ER status, but not by ancestry. However, differential methylation analysis identified 157 CpG loci with a mean β value difference of at least 0.17 between races, with almost twice as many differences in ER-negative tumors compared to ER-positive cancers. This first genome-wide methylation study to address disparities indicates that there are likely differing etiologic pathways for the development of ER negative breast cancer between AA and EA women. Further investigation of the genes most differentially methylated by race in ER negative tumors can guide new approaches for cancer prevention and targeted therapies, and elucidate the biologic basis of breast cancer disparities.

  18. Causal Therapy of Breast Cancer Irrelevant of Age, Tumor Stage and 
ER-Status: Stimulation of Estrogen Signaling Coupled With Breast 
Conserving Surgery

    PubMed Central

    Suba, Zsuzsanna

    2016-01-01

    Abstract: Background Results of long-term studies justify that the rate of breast cancer recurrence and tumor-related mortality remains quite unpredictable, regardless of the use of any current therapeutic measures. Objective Since the application of standard therapies, such as surgery, radiation, chemotherapy and antiestrogen administration does not work as might be expected; our therapeutic practice requires thorough rethinking. Method Published long-term therapeutic results on breast cancer cases were analyzed in correlation with stage at diagnosis, ER-status of tumors and patients’ age. The effectiveness of current therapeutic measures was also compared by estimating the rate of tumor-free survival, breast cancer recurrence and breast cancer-specific mortality. Results Diagnosis and treatment of breast cancer at an early stage cannot improve the rate of tumor-free survival. Poor differentiation of tumors, ER-negativity in particular, defines poor prognosis even after applying aggressive therapies. In patients treated with in situ breast cancer, the recurrence-rate of invasive tumor increased directly with ageing irrespective of tumor size or ER-status at diagnosis. Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors. Antiestrogen treatment exhibited unforeseeable effectiveness even on targeted ER-positive tumors. Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumor-growth. Conclusion Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer. PMID:27087654

  19. Characterization of Estrogen-Receptor-Targeted Contrast-Agents in Solution, Breast Cancer Cells and Tumors in vivo

    PubMed Central

    Pais, Adi; Biton, Inbal Eti; Margalit, Raanan; Degani, Hadassa

    2012-01-01

    The estrogen receptor (ER) is a major prognostic biomarker of breast cancer, currently determined in surgical specimens by immunohistochemistry. Two new ER targeted probes, pyridine-tetra-acetate-Gd chelate (PTA-Gd) conjugated either to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd), were explored as contrast agents for molecular imaging of ER. In solution both probes exhibited a micromolar ER binding-affinity, fast water exchange-rate (~107s−1) and water proton-relaxivity of 4.7 to 6.8 mM−1s−1. In human breast cancer cells, both probes acted as estrogen agonists and enhanced the water protons T1 relaxation-rate and relaxivity in ER-positive as compared to ER-negative cells, with EPTA-Gd showing a higher ER-specific relaxivity than TPTA-Gd. In studies of breast cancer tumors in vivo EPTA-Gd induced the highest enhancement in ER-positive tumors as compared to ER-negative tumors and muscle tissue, enabling in vivo detection of ER. TPTA-Gd demonstrated the highest enhancement in muscle tissue indicating non specific interaction of this agent with muscle components. The extracellular contrast agents, PTA-Gd and GdDTPA, showed no difference in the perfusion capacity of ER-positive and negative tumors confirming the specific interaction of EPTA-Gd with ER. These findings lay a basis for the molecular imaging of the estrogen receptor using EPTA-Gd as a template for further developments. PMID:22887470

  20. Macroscopic Stiffness of Breast Tumors Predicts Metastasis

    PubMed Central

    Fenner, Joseph; Stacer, Amanda C.; Winterroth, Frank; Johnson, Timothy D.; Luker, Kathryn E.; Luker, Gary D.

    2014-01-01

    Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer. PMID:24981707

  1. Augmented reality for breast tumors visualization.

    PubMed

    Ghaderi, Mohammad Ali; Heydarzadeh, Mehrdad; Nourani, Mehrdad; Gupta, Gopal; Tamil, Lakshman

    2016-08-01

    3D visualization of breast tumors are shown to be effective by previous studies. In this paper, we introduce a new augmented reality application that can help doctors and surgeons to have a more accurate visualization of breast tumors; this system uses a marker-based image-processing technique to render a 3D model of the tumors on the body. The model can be created using a combination of breast 3D mammography by experts. We have tested the system using an Android smartphone and a head-mounted device. This proof of concept can be useful for oncologists to have a more effective screening, and surgeons to plan the surgery.

  2. 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

  3. Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen

    PubMed Central

    2011-01-01

    Introduction We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients

  4. Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

    PubMed Central

    Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru A.; Newcomb, Polly A.; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F.

    2016-01-01

    Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into

  5. 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.

  6. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2008-07-01

    component involved application and further refinement of optical tomographic imaging using independent component analysis ( OPTICA ) for locating and cross...section imaging of a tumor in a model cancerous breast assembled using ex vivo breast tissue specimens. The OPTICA approach was able to detect...infrared imaging, optical tomography using independent component analysis ( OPTICA ), training, molecular imaging, cancer biology 16. SECURITY

  7. Freehand 3D ultrasound breast tumor segmentation

    NASA Astrophysics Data System (ADS)

    Liu, Qi; Ge, Yinan; Ou, Yue; Cao, Biao

    2007-12-01

    It is very important for physicians to accurately determine breast tumor location, size and shape in ultrasound image. The precision of breast tumor volume quantification relies on the accurate segmentation of the images. Given the known location and orientation of the ultrasound probe, We propose using freehand three dimensional (3D) ultrasound to acquire original images of the breast tumor and the surrounding tissues in real-time, after preprocessing with anisotropic diffusion filtering, the segmentation operation is performed slice by slice based on the level set method in the image stack. For the segmentation on each slice, the user can adjust the parameters to fit the requirement in the specified image in order to get the satisfied result. By the quantification procedure, the user can know the tumor size varying in different images in the stack. Surface rendering and interpolation are used to reconstruct the 3D breast tumor image. And the breast volume is constructed by the segmented contours in the stack of images. After the segmentation, the volume of the breast tumor in the 3D image data can be obtained.

  8. A Giant Phyllodes Tumor of the Breast

    PubMed Central

    Schillebeeckx, Charlotte; Verbeeck, Guy; Daenen, Geert; Servaes, Dirk; Bronckaers, Marc

    2016-01-01

    Phyllodes tumors of the breast are rare, accounting for less than 1% of the breast tumors. They are mostly seen in women between 45 and 49 years old. These are fast growing tumors with a large spectrum of behavior (from benign to metastatic) and can resemble fibroadenomas. Correct diagnosis mostly through core needle biopsy is important to decide whether a surgical excision has to be done. Here we report a case of a 57-year-old woman with a fast growing, ulcerated tumor in the left breast. Core needle biopsy suggested a malignant phyllodes tumor with heterologous liposarcomatous differentiation. Treatment with total mastectomy and adjuvant radiotherapy followed. Primary treatment is always surgery, whether radiotherapy or chemotherapy has to follow remains uncertain. There is a high-recurrence rate, especially when the surgical margins are narrow. PMID:27746880

  9. 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.

  10. The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer.

    PubMed

    Wellberg, Elizabeth A; Checkley, L Allyson; Giles, Erin D; Johnson, Stevi J; Oljira, Robera; Wahdan-Alaswad, Reema; Foright, Rebecca M; Dooley, Greg; Edgerton, Susan M; Jindal, Sonali; Johnson, Ginger C; Richer, Jennifer K; Kabos, Peter; Thor, Ann D; Schedin, Pepper; MacLean, Paul S; Anderson, Steven M

    2017-07-24

    The androgen receptor (AR) has context-dependent roles in breast cancer growth and progression. Overall, high tumor AR levels predict a favorable patient outcome, but several studies have established a tumor promotional role for AR, particularly in supporting the growth of estrogen receptor positive (ER-positive) breast cancers after endocrine therapy. Our previous studies have demonstrated that obesity promotes mammary tumor progression after ovariectomy (OVX) in a rat model of postmenopausal breast cancer. Here, we investigated a potential role for AR in obesity-associated post-OVX mammary tumor progression following ovarian estrogen loss. In this model, we found that obese but not lean rats had nuclear localized AR in tumors that progressed 3 weeks after OVX, compared to those that regressed. AR nuclear localization is consistent with activation of AR-dependent transcription. Longer-term studies (8 weeks post-OVX) showed that AR nuclear localization and expression were maintained in tumors that had progressed, but AR expression was nearly lost in tumors that were regressing. The anti-androgen enzalutamide effectively blocked tumor progression in obese rats by promoting tumor necrosis and also prevented the formation of new tumors after OVX. Neither circulating nor mammary adipose tissue levels of the AR ligand testosterone were elevated in obese compared to lean rats; however, IL-6, which we previously reported to be higher in plasma from obese versus lean rats, sensitized breast cancer cells to low levels of testosterone. Our study demonstrates that, in the context of obesity, AR plays a role in driving ER-positive mammary tumor progression in an environment of low estrogen availability, and that circulating factors unique to the obese host, including IL-6, may influence how cancer cells respond to steroid hormones.

  11. 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

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

    USDA-ARS?s Scientific Manuscript database

    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...

  13. Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

    PubMed

    Flote, Vidar G; Vettukattil, Riyas; Bathen, Tone F; Egeland, Thore; McTiernan, Anne; Frydenberg, Hanne; Husøy, Anders; Finstad, Sissi E; Lømo, Jon; Garred, Øystein; Schlichting, Ellen; Wist, Erik A; Thune, Inger

    2016-03-12

    High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No

  14. [Phyllodes breast tumors: apropos 2 cases].

    PubMed

    Bruzzese, A; Chiarini, S; Pasquino, C; Favoriti, M; Stella, S

    1995-01-01

    The observation of two cases of phyllode tumors of the breast, one benign and the other malignant, brought the Authors to focus the fundamental aspects of these neoplasias. The histologic coexistence of both epithelial and connectival components, a relative unpredictable clinical evolution, the high frequency of recurrences, the stromal hyperproduction and modifications as expression of malignancy, and the need for large excisions are the fundamental characteristics of these tumors, which are considered transitional forms between benignity and malignancy.

  15. Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis

    DTIC Science & Technology

    2004-09-01

    AD_ Award Number: DAMD17-00-1-0459 TITLE: Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis...SUBTITLE 5. FUNDING NUMBERS Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key DAMD17-00-1-0459 to Tumor Therapy Planning and Tumor Prognosis 6...research project is to develop and evaluate a new approach to monitoring of oxygenated hemoglobin concentration (HbO 2) of breast tumors under

  16. 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

  17. 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

  18. 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.

  19. ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients

    PubMed Central

    Chu, David; Paoletti, Costanza; Gersch, Christina; VanDenBerg, Dustin A.; Zabransky, Daniel J.; Cochran, Rory L.; Wong, Hong Yuen; Toro, Patricia Valda; Cidado, Justin; Croessmann, Sarah; Erlanger, Bracha; Cravero, Karen; Kyker-Snowman, Kelly; Button, Berry; Parsons, Heather; Dalton, W. Brian; Gillani, Riaz; Medford, Arielle; Aung, Kimberly; Tokudome, Nahomi; Chinnaiyan, Arul M.; Schott, Anne; Robinson, Dan; Jacks, Karen S.; Lauring, Josh; Hurley, Paula; Hayes, Daniel F.; Rae, James; Park, Ben Ho

    2016-01-01

    Purpose Mutations in the estrogen receptor-alpha (ER) gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Due to limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from metastatic breast cancer patients. Experimental Design We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild type ESR1 identified by next generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital polymerase chain reaction (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS and ptDNA ESR1 mutations were analyzed by ddPCR. Results In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in six of twelve patients (50%). Conclusions We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion. PMID:26261103

  20. Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0056 TITLE: Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression PRINCIPAL...to 09-29-2016 4. TITLE AND SUBTITLE Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression 5a. CONTRACT NUMBER 5b...previously established a positive correlation between a fibrotic phenotype in human breast tumors — especially the HER2 and Basal-like breast cancer subtypes

  1. Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth.

    PubMed

    Sharma, Shweta; Kotamraju, Venkata Ramana; Mölder, Tarmo; Tobi, Allan; Teesalu, Tambet; Ruoslahti, Erkki

    2017-03-08

    Antiangiogenic and vascular disrupting compounds have shown promise in cancer therapy, but tend to be only partially effective. We previously reported a potent theranostic nanosystem that was highly effective in glioblastoma and breast cancer mouse models, retarding tumor growth and producing some cures [ Agemy , L. et al. Proc. Natl. Acad. Sci. U.S.A. 2011 , 108 , 17450 - 17455 . Agemy , L. et al. Mol. Ther. 2013 , 21 , 2195 - 2204 .]. The nanosystem consists of iron oxide NPs ("nanoworms") coated with a composite peptide with tumor-homing and pro-apoptotic domains. The homing component targets tumor vessels by binding to p32/gC1qR at the surface or tumor endothelial cells. We sought to further improve the efficacy nanosystem by searching for an optimally effective homing peptide that would also incorporate a tumor-penetrating function. To this effect, we tested a panel of candidate p32 binding peptides with a sequence motif that conveys tumor-penetrating activity (CendR motif). We identified a peptide designated as Linear TT1 (Lin TT1) (sequence: AKRGARSTA) as most effective in causing tumor homing and penetration of the nanosystem. This peptide had the lowest affinity for p32 among the peptides tested. The low affinity may have moderated the avidity effect from the multivalent presentation on nanoparticles (NPs), such that the NPs avoid getting trapped by the so-called "binding-site barrier", which can hinder tissue penetration of compounds with a high affinity for their receptors. Treatment of breast cancer mice with the LinTT1 nanosystem showed greatly improved efficacy compared to the original system. These results identify a promising treatment modality and underscore the value of tumor penetration effect in improving the efficacy tumor treatment.

  2. Cytokine pattern of the breast tumor supernatant.

    PubMed

    Autenshlyus, A I; Kunts, T A; Karpukhina, K V; Mikhaylova, E S; Varaksin, N A; Marinkin, I O; Lyakhovich, V V

    2016-09-01

    Cytokine production was evaluated in supernatants of cultured tumor cells that were obtained by biopsy of the breast invasive ductal carcinoma (IDC) and breast fibroadenoma (FA) and grown in vitro. In the IDC supernatants, the concentrations of pro-inflammatory (pro-oncogenic) cytokines IL-17, IL-18, and IFNγ and of IL-1 receptor antagonist were significantly higher than in the FA cell supernatants. The concentrations of anti-inflammatory cytokine IL-10 and MCP-1 protein in supernatants of IDC cells were significantly lower than those determined in FA supernatants.

  3. Circulating tumor cells in breast cancer

    PubMed Central

    Pukazhendhi, Geetha; Glück, Stefan

    2014-01-01

    Circulating tumor cell (CTC) measurement in peripheral blood of patients with breast cancer offers prognostic information. In this review, we will try to identify evidence that could be used for prognosis, predictive power to draw this tool to clinical utility. We reviewed 81 manuscripts, and categorized those in discovery datasets, prognostic factors in metastatic breast cancer, identification of clinical utility in early breast cancer and in novel approaches. With each patient responding differently to chemotherapy, more efficient markers would improve clinical outcome. Current CTC diagnostic techniques use epithelial markers predominantly; however, the most appropriate method is the measurement of circulating DNA. It has been hypothesized that micrometastasis occurs early in the development of tumors. That implies the presence of CTCs in nonmetastatic setting. The origin of stimulus for malignant transformation is yet unknown. The role of microenvironment as a stimulus is also being investigated. It has been shown that CTCs vary in numbers with chemotherapy. The markers, which are followed-up in the primary tumors, are also being studied on the CTCs. There is discordance of the human epidermal growth factor receptor-2 status between the primary tumor and CTCs. This review summarizes our current knowledge about the CTCs. With genetic profiling and molecular characterization of CTCs, it is possible to overcome the diagnostic difficulties. Evidence for clinical utility of CTC as prognostic and predictive marker is increasing. Appropriate patient stratification according to CTC determination among other tests, would make personalized cancer therapy more feasible. PMID:25191136

  4. Phyllodes tumor of the breast: an update.

    PubMed

    Tse, Gary M K; Niu, Yun; Shi, Hui-Juan

    2010-01-01

    Phyllodes tumor is an uncommon biphasic breast tumor, with the ability to recur and metastasize, and it behaves biologically like a stromal neoplasm. Traditionally, phyllodes tumors are graded by the use of a set of histologic data into benign, borderline, and malignant. In most series, all phyllodes tumors may recur, but only the borderline and malignant phyllodes tumors metastasize. On the basis of histologic features, prediction of behavior is difficult. The expression of many biological markers, including p53, hormone receptors, proliferation markers, angiogenesis group of markers, c-kit, CD10 and epidermal growth factor receptor have been explored, and many have been shown to be variably expressed, depending on the grade of the tumor. These markers are, however, of limited value in predicting the behavior of the tumor. Recently investigators have reported a plethora of genetic changes in phyllodes tumors, the most consistent of which seems to be 1q gain by comparative genomic hybridization. Some candidate genes have been mapped to various sites, and preliminary data suggest that some of these changes may be related to recurrence. It is foreseeable that more exciting data will be generated to help us to understand the etiology and pathogenesis of phyllodes tumor.

  5. Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

    DTIC Science & Technology

    2006-04-01

    DAMD17-02-1-0457 TITLE: Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors PRINCIPAL INVESTIGATOR: Michael G...Which Target Neovasculature of Breast Tumors 5b. GRANT NUMBER DAMD17-02-1-0457 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER... breast model resulted in significant delay of tumor growth, by ~50%. In addition, tumors completely regressed in 3/6 (50%) of treated mice. In the

  6. An Integrated Bioinformatics Approach Identifies Elevated Cyclin E2 Expression and E2F Activity as Distinct Features of Tamoxifen Resistant Breast Tumors

    PubMed Central

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M.; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers. PMID:21789246

  7. An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors.

    PubMed

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers.

  8. Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo.

    PubMed

    Reddy, Kaladhar B; Glaros, Selina

    2007-04-01

    Elevated expression of mitogen-activated protein kinase (Erk/MAPK) has been noted in a significant percentage of primary human breast cancers. To directly assess the importance of Erk/MAPK activation in estrogen (E2)-induced tumor progression, we blocked E2-signaling with MEK-inhibitor CI-1040 and/or tamoxifen (Tam). Our data show that both MEK-inhibitor CI-1040 and Tam blocked E2-induced MAPK phosphorylation and cell proliferation in MCF-7 breast cancer cells in vitro. However, in vivo studies show that anti-tumor efficacy of combining the CI-1040 and Tam was similar to single agent(s). Furthermore, sequential treatment with Tam followed by CI-1040 or CI-1040 followed by Tam did not significantly reduce E2-induced tumor growth. This suggests that the combination of CI-1040 and Tam may not be synergistic in inhibiting E2-induced tumor growth. However, these findings also indicate that MAPK plays a critical role in E2-induced tumor growth, and that this could be a potential therapeutic target to combat hormonally regulated growth in ER-positive tumors.

  9. Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor.

    PubMed

    Colleoni, M; Li, S; Gelber, R D; Coates, A S; Castiglione-Gertsch, M; Price, K N; Lindtner, J; Rudenstam, C-M; Crivellari, D; Collins, J; Pagani, O; Simoncini, E; Thürlimann, B; Murray, E; Forbes, J; Erzen, D; Holmberg, S; Veronesi, A; Goldhirsch, A

    2005-05-01

    Controversy persists about whether chemotherapy benefits all breast cancer patients. In the International Breast Cancer Study Group (IBCSG) trial VII, 1212 postmenopausal patients with node-positive disease were randomized to receive tamoxifen for 5 years or tamoxifen plus three concurrent courses of cyclophosphamide, methotrexate and 5-fluorouracil ('classical' CMF) chemotherapy, either early, delayed or both. In IBCSG trial IX, 1669 postmenopausal patients with node-negative disease were randomized to receive either tamoxifen alone or three courses of adjuvant classical CMF prior to tamoxifen. Results were assessed according to estrogen receptor (ER) content of the primary tumor. For patients with node-positive, ER-positive disease, adding CMF either early, delayed or both reduced the risk of relapse by 21% (P=0.06), 26% (P=0.02) and 25% (P=0.02), respectively, compared with tamoxifen alone. There was no difference in disease-free survival when CMF was given prior to tamoxifen in patients with node-negative, ER-positive tumors. CMF given concurrently (early, delayed or both) with tamoxifen was more effective than tamoxifen alone for patients with node-positive, endocrine-responsive breast cancer, supporting late administration of chemotherapy even after commencement of tamoxifen. In contrast, sequential CMF and tamoxifen for patients with node-negative, endocrine-responsive disease was ineffective.

  10. Genomic Heterogeneity of Breast Tumor Pathogenesis

    PubMed Central

    Ellsworth, Rachel E.; Hooke, Jeffrey A.; Shriver, Craig D.; Ellsworth, Darrell L.

    2009-01-01

    Pathological grade is a useful prognostic factor for stratifying breast cancer patients into favorable (low-grade, well-differentiated tumors) and less favorable (high-grade, poorly-differentiated tumors) outcome groups. Under the current system of tumor grading, however, a large proportion of tumors are characterized as intermediate-grade, making determination of optimal treatments difficult. In an effort to increase objectivity in the pathological assessment of tumor grade, differences in chromosomal alterations and gene expression patterns have been characterized in low-grade, intermediate-grade, and high-grade disease. In this review, we outline molecular data supporting a linear model of progression from low-grade to high-grade carcinomas, as well as contradicting genetic data suggesting that low-grade and high-grade tumors develop independently. While debate regarding specific pathways of development continues, molecular data suggest that intermediate-grade tumors do not comprise an independent disease subtype, but represent clinical and molecular hybrids between low-grade and high-grade tumors. Finally, we discuss the clinical implications associated with different pathways of development, including a new clinical test to assign grade and guide treatment options. PMID:20689613

  11. A Rare Breast Tumor: Dermatofibrosarcoma Protuberans

    PubMed Central

    Özcan, Tevhide Bilgen; Hacıhasanoğlu, Ezgi; Nazlı, Mehmet Ali; Aksoy, Şefika; Leblebici, Cem; Talu, Canan Kelten

    2016-01-01

    Dermatofibrosarcoma protuberans is a slow-growing, local aggressive fibrous tumor of the subcutaneous tissue, frequently seen in the proximal extremities and the trunk. Its occurrence in the breast is very rare. Herein, we present a female who presented with a breast mass, and aim to discuss pathological features and differential diagnosis of dermatofibrosarcoma protuberans. A 44-year-old female presented to our clinic with a mass on her breast. Physical examination revealed a 8×5.5 cm mass with multilobular nodules on the skin in the lower inner quadrant of her right breast. Her mammography revealed a hyperdense, 7.5×6.5 cm, well-demarcated, lobulated mass in the right breast, which caused nodules on the lower para-areolar portion of the breast skin. There was no axillary lymphadenopathy on both clinical and radiologic examinations. A core needle biopsy had been performed prior to her referral to our center, which revealed a ‘spindle cell lesion’. The patient underwent simple mastectomy. On macroscopic examination; the skin over the lesion appeared ulcerated, and there was a well-defined solid mass, which was pale white-tan on the cut surface. Microscopic examination revealed monotonous spindle cell proliferation arranged in storiform pattern within the collagenous stroma with irregular extensions into deep adipose tissue. There were no necrosis or nuclear pleomorphism. The mitotic rate was 2–3/10 HPF. Immunohistochemically tumor cells showed diffuse CD34 positivity, and S100, EMA and SMA negativity. Based on histopathological and immunohistochemical findings, the lesion was diagnosed as dermatofibrosarcoma protuberans. Local recurrence is expected in 20–50% of these cases. Its treatment requires complete surgical excision with wide margins. Distant metastases, although rare, have been reported.

  12. IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells

    PubMed Central

    Freund, Ariane; Chauveau, Corine; Brouillet, Jean-Paul; Lucas, Annick; Lacroix, Matthieu; Licznar, Anne; Vignon, Françoise; Lazennec, Gwendal

    2003-01-01

    Estrogen receptor (ER) status is an important parameter in breast cancer management as ER-positive breast cancers have a better prognosis than ER-negative tumors. This difference comes essentially from the lower aggressiveness and invasiveness of ER-positive tumors. Here, we demonstrate, that IL-8 was clearly overexpressed in most ER-negative breast, ovary cell lines and breast tumor samples tested, whereas no significant IL-8 level could be detected in ER-positive breast or ovarian cell lines. We have also cloned human IL-8 from ER-negative MDA-MB-231 cells and we show that IL-8 produced by breast cancer cells is identical to monocyte-derived IL-8. Interestingly, the invasion potential of ER-negative breast cancer cells is associated at least in part with expression of interleukin-8 (IL-8), but not with IL-8 receptors levels. Moreover, IL-8 increases the invasiveness of ER-positive breast cancer cells by 2 fold, thus confirming the invasion-promoting role of IL-8. On the other hand, exogenous expression of estrogen receptors in ER-negative cells led to a decrease of IL-8 levels. In summary, our data show that IL-8 expression is negatively linked to ER-status of breast and ovarian cancer cells. We also support the idea that IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness. PMID:12527894

  13. Collision tumor with inflammatory breast carcinoma and malignant phyllodes tumor: a case report and literature review.

    PubMed

    Shin, Young Duck; Lee, Seul Kee; Kim, Kyu Sun; Park, Mi Ja; Kim, Joo Heon; Yim, Hyun Sun; Choi, Young Jin

    2014-01-08

    There have been some reports of coincidental presentation of breast carcinoma and phyllodes tumor in the same breast. Most of the cases were carcinoma that arose from a phyllodes tumor with a histologically identified transitional area, and they behaved less aggressively than the usually encountered carcinoma. Collision tumors are rare clinical entities in which two histologically distinct tumor types show involvement at the same site. The occurrence of these tumors in the breast is extremely rare. Here, we report a case of 45-year-old woman who had both invasive ductal carcinoma as the finding of inflammatory carcinoma and a malignant phyllodes tumor in the same breast. There was no evidence of a transitional area between the phyllodes tumor and the invasive ductal carcinoma. To our knowledge, this is the first report of a collision tumor of inflammatory breast carcinoma coincident with a malignant phyllodes tumor in same breast.

  14. Matrine Suppresses the ER-positive MCF Cells by Regulating Energy Metabolism and Endoplasmic Reticulum Stress Signaling Pathway.

    PubMed

    Xiao, Yi; Ma, Dachang; Wang, Honglei; Wu, Duoming; Chen, Ying; Ji, Kun; Qin, Tao; Wu, Li

    2017-04-01

    Matrine (C15 H24 N2 O), an alkaloid that is one of the main active components from Sophora flavescens. Matrine has been demonstrated to have therapeutic effects on various solid tumors, including breast cancer, but the mechanism still needs further study. Endoplasmic reticulum (ER)-positive Michigan Cancer Foundation cells were cultured, and matrine was added in various amounts to measure the dose-dependent and time-dependent cytotoxicity. Hoechst 33258 staining was used to observed nuclear morphological changes. Apoptosis was measured by AnnexinV/PI double staining assay kit. Intracellular adenosine triphosphate and glycometabolism were detected by assay kit. The protein levels GRP78, p-eIF2α, CHOP, cytochrome c, and HexokinaseII were analyzed. Mechanistic investigations revealed that matrine treatment causes ER dilation and up-regulated the expression of ER stress markers GRP78, eIF2α, and CHOP, increases the levels of apoptotic in Michigan Cancer Foundation cells, subsequently, blocking the ER stress-mediated apoptosis pathway, significantly decreased matrine-induced apoptotic but still has significant difference between control group. In addition, matrine not only promoted the occurrence of ER stress but also inhibited the expression of hexokinase II, down-regulated energy metabolism. In summary, the present study suggests that the induction of ER stress-mediated apoptosis by matrine and down-regulated energy metabolism may account for its cytotoxic effects in human breast cancer cells. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  15. Drug Helps Fight Breast Tumors Tied to 'Cancer Genes'

    MedlinePlus

    ... Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' Lynparza may offer a new treatment for women ... with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study. Olaparib delayed cancer ...

  16. Location of triple-negative breast cancers: comparison with estrogen receptor-positive breast cancers on MR imaging.

    PubMed

    Kim, Won Hwa; Han, Wonshik; Chang, Jung Min; Cho, Nariya; Park, In Ae; Moon, Woo Kyung

    2015-01-01

    There has been a major need to better understand the biological characteristics of triple-negative breast cancers. Compared with estrogen receptor (ER)-positive cancers, several magnetic resonance (MR) imaging findings have been reported as characteristic findings. However, information regarding their location has not been described. Our study was to compare the location of triple-negative breast cancers with that of ER-positive breast cancers using magnetic resonance (MR) imaging. The locations of 1102 primary breast cancers (256 triple-negative and 846 ER-positive) in 1090 women (mean, 52.1 years) were reviewed using three-dimensional (3D) coordinates. The x-axis measurement was recorded as the transverse distance from the posterior nipple line; y-axis measurement as the anteroposterior distance from the chest wall; z-axis measurement as the superoinferior distance from the posterior nipple line. The association between breast cancer subtype and tumor location was evaluated using multiple linear regression analysis. Triple-negative breast cancers were significantly closer to the chest wall than ER-positive breast cancers in absolute (1.8 cm vs. 2.3 cm, P < .0001) and normalized (0.21 vs. 0.25, P < .0001) y-axis distances. The x- and z-axes distances were not significantly different between triple-negative and ER-positive breast cancers. Multiple linear regression analysis revealed that age, mammographic density, axillary nodal status, and triple-negative subtype were significantly associated with absolute and normalized distances from the chest wall (all P < .05). Our results show that triple-negative breast cancers have a tendency toward a posterior or prepectoral location compared with ER-positive breast cancers.

  17. Malignant phyllodes tumor of the breast: a case study.

    PubMed

    Keim-Malpass, Jessica; Mills, Anne M; Showalter, Shayna L

    2014-10-01

    Malignant phyllodes tumors of the breast are rare, fast-growing tumors that can be difficult to diagnose. A case study is featured about a young adult patient who lacked insurance and received a delayed diagnosis of malignant phyllodes tumor of the breast. This article includes pertinent clinical and age-specific considerations for comprehensive management.

  18. [Papillary tumors of the breast].

    PubMed

    Hungermann, D; Decker, T; Bürger, H; Kersting, C; Böcker, W

    2006-09-01

    The term papilloma applies to benign proliferative epithelial breast lesions with a papillary architecture. The papillae in such lesions contain an arborizing fibrovascular core, glandular surface epithelium and a basal myoepithelial layer. A basement membrane encloses these structures. Papilloma may occur at any site in the ductal lobular system and according to its localization is subdivided into two types: solitary (central) papilloma which are located in the major nipple/subareolar ducts or large segmental ducts and multiple (peripheral) papillomas in cystically dilated terminal ductal lobular units (TDLU). Stromal changes, epithelial metaplasia and/or proliferations and neoplasia may alter the prototypical architecture. In a significant number of papillomas atypia can be identified which have to be classified as atypical proliferates of the ductal type. These lesions must be distinguished from the papillary type of ductal carcinoma in situ. Some 17% of all papilloma are associated with (synchronous) intraductal or invasive carcinoma, but these also act as an indicator for subsequent (metachronous) carcinoma. As a consequence, in minimally invasive biopsy papilloma has to be classified as B3 and usually has to be followed by surgical excision.

  19. Characterization of Gene Expression in Human Breast Tumor Endothelium

    DTIC Science & Technology

    2008-05-01

    to UV-induced apoptosis in primary culture of canine mammary gland tumors (7), and SFRP2 decreased apoptosis in cardiomyocytes exposed to hypoxia(8...microdissection (LCM) of vascular cells from frozen human breast tumors and normal breast tissue for genomic analysis. We found SFRP2 to have 6 fold increased...vascular cells from frozen human breast tumors , where the RNA was of high quality and sufficient for genomic analysis(6). We found 55 genes with > 4

  20. Do mammographic tumor features in breast cancer relate to breast density and invasiveness, tumor size, and axillary lymph node involvement?

    PubMed

    Sartor, Hanna; Borgquist, Signe; Hartman, Linda; Olsson, Åsa; Jawdat, Faith; Zackrisson, Sophia

    2015-05-01

    Breast density and mammographic tumor features of breast cancer may carry prognostic information. The potential benefit of using the combined information obtained from breast density, mammographic tumor features, and pathological tumor characteristics has not been extensively studied. To investigate how mammographic tumor features relate to breast density and pathological tumor characteristics. This retrospective study was carried out within the Malmö Diet and Cancer Study: a population-based cohort study recruiting 17,035 women during 1991-1996. A total of 826 incident breast cancers were identified during follow-up. Mammography images were collected and analyzed according to breast density and tumor features at diagnosis. Pathological data were retrieved from medical reports. Mammographic tumor features in relation to invasiveness, tumor size, and axillary lymph node involvement were analyzed using logistic regression yielding odds ratios (OR) with 95% confidence intervals (CI) and adjusted for age at diagnosis, mode of detection, and breast density. Tumors presenting as an ill-defined mass or calcifications were more common in dense breasts than tumors presenting as a distinct mass or with spiculated appearance. Invasive cancer was more common in tumors with spiculated appearance than tumors presenting as a distinct mass (adjusted OR, 5.68 [1.81-17.84]). Among invasive tumors, an ill-defined mass was more often large (>20 mm) compared with a distinct mass, (adjusted OR, 3.16 [1.80-5.55]). Tumors presenting as an ill-defined mass or calcifications were more common in dense breasts. Spiculated appearance was related to invasiveness, and ill-defined mass to larger tumor size, regardless of mode of detection and breast density. The potential role of mammographic tumor features in clinical decision-making warrants further investigation. © The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  1. Molecular biology of breast tumors and prognosis.

    PubMed

    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.

  2. 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

  3. Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications.

    PubMed

    Macciò, Antonio; Madeddu, Clelia; Gramignano, Giulia; Mulas, Carlo; Floris, Carlo; Massa, Daniela; Astara, Giorgio; Chessa, Paola; Mantovani, Giovanni

    2010-07-01

    Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.

  4. PLC-β2 is modulated by low oxygen availability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential.

    PubMed

    Brugnoli, Federica; Grassilli, Silvia; Al-Qassab, Yasamin; Capitani, Silvano; Bertagnolo, Valeria

    2016-12-01

    Limited oxygen availability plays a critical role in the malignant progression of breast cancer by orchestrating a complex modulation of the gene transcription largely dependent on the tumor phenotype. Invasive breast tumors belonging to different molecular subtypes are characterized by over-expression of PLC-β2, whose amount positively correlates with the malignant evolution of breast neoplasia and supports the invasive potential of breast tumor cells. Here we report that hypoxia modulates the expression of PLC-β2 in breast tumor cells in a phenotype-related manner, since a decrease of the protein was observed in the BT-474 and MCF7 cell lines while an increase was revealed in MDA-MB-231 cells as a consequence of low oxygen availability. Under hypoxia, the down-modulation of PLC-β2 was mainly correlated with the decrease of the EMT marker E-cadherin in the BT-474 cells and with the up-regulation of the stem cell marker CD133 in MCF7 cells. The increase of PLC-β2 induced by low oxygen in MDA-MB-231 cells supports the hypoxia-related reorganization of actin cytoskeleton and sustains invasion capability. In all examined cell lines, but with an opposite role in the ER-positive and ER-negative cells, PLC-β2 was involved in the hypoxia-induced increase of HIF-1α, known to affect both EMT and CD133 expression. Our data include PLC-β2 in the complex and interconnected signaling pathways induced by low oxygen availability in breast tumor cells and suggest that the forced modulation of PLC-β2 programmed on the basis of tumor phenotype may prevent the malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia. © 2016 Wiley Periodicals, Inc.

  5. Mammographic Breast Density and Subsequent Risk of Breast Cancer in Postmenopausal Women According to Tumor Characteristics

    PubMed Central

    Yaghjyan, Lusine; Colditz, Graham A.; Collins, Laura C.; Schnitt, Stuart J.; Rosner, Bernard; Vachon, Celine

    2011-01-01

    Background Few studies that investigated the associations between breast density and subsequent breast cancer according to tumor characteristics have produced inconclusive findings. We aimed to determine whether the associations between breast density and subsequent breast cancer varied by tumor characteristics. Methods We included 1042 postmenopausal women diagnosed with breast cancer between June 1, 1989, and June 30, 2004, and 1794 matched control subjects from the Nurses’ Health Study, an ongoing prospective cohort study of 121 701 registered female nurses across the United States. Breast density was estimated from digitized images using computerized techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires before the date of cancer diagnosis for case subjects and matched control subjects. Polychotomous logistic regression was used to assess associations of breast density with tumor subtypes based on invasiveness, histology, size, grade, receptor status, and involvement of lymph nodes. All tests of statistical significance were two-sided. Results The risk of breast cancer increased progressively with increase in percent breast density (Ptrend < .001). Women with higher breast density (≥50%) showed a 3.39-fold (odds ratio = 3.39, 95% confidence interval = 2.46 to 4.68) increased risk of breast cancer compared with women with lower breast density (<10%). The associations between breast density and breast cancer risk were stronger for in situ compared with invasive tumors (Pheterogeneity < .01), high-grade compared with low-grade tumors (Pheterogeneity = .02), larger (>2 cm) compared with smaller (≤2 cm) tumors (Pheterogeneity < .01), and estrogen receptor–negative compared with estrogen receptor–positive tumors (Pheterogeneity = .04). There were no differences in associations by tumor histology, involvement of lymph nodes, and progesterone receptor and HER2 status (Pheterogeneity > .05). Conclusions

  6. Pten in the Breast Tumor Microenvironment: Modeling Tumor-Stroma Co-Evolution

    PubMed Central

    Wallace, Julie A.; Li, Fu; Leone, Gustavo; Ostrowski, Michael C.

    2010-01-01

    Solid human tumors and their surrounding microenvironment are hypothesized to co-evolve in a manner that promotes tumor growth, invasiveness and spread. Mouse models of cancer have focused on genetic changes in the epithelial tumor cells and therefore have not robustly tested this hypothesis. We have recently developed a murine breast cancer model that ablates the PTEN tumor suppressor pathway in stromal fibroblasts. Remarkably, the model resembles human breast tumors both at morphologic and molecular levels. We propose that such models reflect subtypes of tumor-stromal co-evolution relevant to human breast cancer, and will therefore be useful in defining the mechanisms that underpin tumor-stroma crosstalk. Additionally, these models should also aid in molecularly classifying human breast tumors based on both the microenvironment subtypes they contain as well as on the tumor subtype. PMID:21303970

  7. Melanocytic Malignant Peripheral Nerve Sheath Tumor of the Male Breast.

    PubMed

    Wang, Haijun; Ge, Jing; Chen, Lirong; Xie, Panpan; Chen, Fangfang; Chen, Yiding

    2009-01-01

    SUMMARY: BACKGROUND: Malignant peripheral nerve sheath tumors are rare tumor entities that originate from peripheral nerve sheaths and have an unfavorable prognosis. Common sites include deeper soft tissues, usually in the proximity of a nerve trunk. Breast is an absolutely rare location of this lesion, and presentation as a breast lump in the male breast is even rarer. CASE REPORT: A 65-year-old man presented with a 6-month history of a painless mass of the left breast. Tissue biopsy was performed. Histopathology revealed a malignant spindle cell tumor which was confirmed to be a melanocytic malignant peripheral nerve sheath tumor on the basis of immunopositivity for HMB45 and S-100. CONCLUSION: There are no generally accepted guidelines for the treatment of malignant peripheral nerve sheath tumors in the male breast. The patient was referred for radiation therapy after simple mastectomy.

  8. Male Malignant Phyllodes Breast Tumor After Prophylactic Breast Radiotherapy and Bicalutamide Treatment: A Case Report.

    PubMed

    Karihtala, Peeter; Rissanen, Tarja; Tuominen, Hannu

    2016-07-01

    Phyllodes tumor in male breast is an exceptionally rare neoplasm with only few published case reports. Herein, we present a case of malignant phyllodes tumor in male breast nine years after prophylactic breast 10 Gy radiotherapy and after nine year bicalutamide treatment. The imaging findings of the tumor and pathological correlation are also presented. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Clinical significance of pretherapeutic Ki67 as a predictive parameter for response to neoadjuvant chemotherapy in breast cancer: is it equally useful across tumor subtypes?

    PubMed

    Sueta, Aiko; Yamamoto, Yutaka; Hayashi, Mitsuhiro; Yamamoto, Satoko; Inao, Toko; Ibusuki, Mutsuko; Murakami, Keiichi; Iwase, Hirotaka

    2014-05-01

    Ki67 has been identified as a prognostic and predictive marker for breast cancer and it was suggested that it may contribute to pathologic complete response (pCR) after neoadjuvant chemotherapy. It is unclear whether expression of Ki67 is particularly helpful for prediction of pCR across tumor subtypes. Pretherapeutic Ki67 was evaluated in a series of 121 breast cancer core biopsies. After neoadjuvant chemotherapy, we used postoperative specimens to evaluate the pCR status. Several parameters predictive of pCR were identified using logistic regression analysis. We investigated subgroups defined by estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, in which predicting pCR with Ki67 might be feasible. Ki67 was found to be an independent predictor of pCR in multivariate analysis (odds ratio [OR], 3.62; 95% CI, 1.21-10.8). When stratified by ER, the above significance was exclusive to ER-positive tumors (OR, 6.24; 95% CI, 1.40-27.7). Using an receiver-operating characteristic curve, we obtained moderate discriminative accuracy with an area under the curve of 0.7752 for Ki67 prediction of pCR in ER-positive tumors. In subgroup analysis, patients with high Ki67 showed significantly improved pCR rate in luminal-type disease, with a median Ki67 value of 43% in the patients who achieved pCR, versus 29% for those without pCR (P = .018), whereas no associations were observed in other subtypes. Our results suggest that stratification according to Ki67 levels might improve predictive significance of the response in hormone-responsive breast cancer. Even in these subtypes assumed to be less chemosensitive, some patients with highly proliferative tumors derive a significant benefit from chemotherapy, and consequently it is important to identify them. Copyright © 2014 Mosby, Inc. All rights reserved.

  10. Expression of cyclooxygenase-2 (COX-2) and p53 in neighboring invasive and in situ components of breast tumors.

    PubMed

    Serra, Katia Piton; Sarian, Luis Otavio; Rodrigues-Peres, Raquel Mary; Vassallo, José; Soares, Fernando Augusto; Pinto, Glauce Aparecida; da Cunha, Isabela Werneck; Shinzato, Julia Yoriko; Derchain, Sophie F M

    2012-05-01

    The aim of the study was to assess the relationship between the expression of COX-2 and p53, hormone receptors and HER-2 in the in situ (DCIS) and invasive components of ductal carcinomas (IDC) of the same breast. The expression of COX-2, p53, and hormone receptors was assessed in 87 cases of IDC with contiguous areas of DCIS. Results showed that there was no difference in COX-2 expression comparing the in situ and invasive components of the tumors. In the in situ component, there was a statistically borderline increase in p53 expression in tumors that also expressed COX-2. ER-positive specimens were more common in the group of tumors that expressed COX-2 in the invasive component. From this study we conclude that the expression of COX-2 was similar in the in situ and invasive components of the breast carcinomas. COX-2 positivity was marginally related with the expression of p53 in the in situ components, and with the ER expression in the invasive components. Copyright © 2011 Elsevier GmbH. All rights reserved.

  11. Expression of cell polarity protein scribble differently affects prognosis in primary tumor and lymph node metastasis of breast cancer patients.

    PubMed

    Sakakibara, Junta; Sakakibara, Masahiro; Shiina, Nobumitsu; Fujimori, Toshihiko; Okubo, Yoshiyuki; Fujisaki, Kaoru; Nagashima, Takeshi; Sangai, Takafumi; Nakatani, Yukio; Miyazaki, Masaru

    2017-05-01

    We evaluated the relationship between the immunohistochemically determined expression of the cell polarity protein scribble to prognosis in different environments of estrogen receptor (ER) expression and epithelial-to-mesenchymal transition (EMT). We immunohistochemically evaluated the expression level of scribble in primary tumors and lymph node metastases of 225 node-positive breast cancer patients who had received chemotherapy. We then evaluated metastasis-free survival (MFS) in the absence or presence of ER and the EMT-related protein vimentin. Among patients with ER-positive tumors, patients with low scribble expression in the primary tumor had a significantly shorter MFS than patients with high scribble expression (p = 0.0225). Furthermore, among patients with vimentin-negative tumors, patients with low expression of scribble in the primary tumor had significantly shorter MFS than patients with high expression of scribble (p = 0.0463). In contrast, among patients with vimentin-positive tumors, patients with high expression of scribble in the primary tumor had significantly shorter MFS than patients with low expression of scribble (p = 0.0343). Moreover, among patients with ER-negative tumors, patients with high expression of scribble in lymph node metastases showed significantly higher expression of E-cadherin in metastases (p = 0.0407) and had significantly shorter MFS than patients with low expression of scribble (p = 0.0064). The prognostic significance of cell polarity depended on the ER expression and EMT. Furthermore, the preservation of cell polarity in metastases was associated with mesenchymal-to-epithelial transition and worse prognosis. Cell polarity promotes the diversity of metastasis in combination with malignancy grade in breast cancer patients.

  12. Anti-tumor effect of Shu-Gan-Liang-Xue decoction in breast cancer is related to the inhibition of aromatase and steroid sulfatase expression.

    PubMed

    Zhou, Ning; Han, Shu-Yan; Zhou, Fei; Li, Ping-ping

    2014-07-03

    Shu-Gan-Liang-Xue Decoction (SGLXD), a traditional Chinese herbal formula used to ameliorate the hot flushes in breast cancer patients, was reported to have anti-tumor effect on breast cancer. Estrogen plays a critical role in the genesis and evolution of breast cancer. Aromatase and steroid sulfatase (STS) are key estrogen synthesis enzymes that predominantly contribute to the high local hormone concentrations. The present study was to evaluate the anti-tumor effect of SGLXD on estrogen receptor (ER) positive breast cancer cell line ZR-75-1, and to investigate its underlying mechanisms both in vitro and in vivo. The anti-tumor activity of SGLXD in vitro was investigated using the MTT assay. The in vivo anti-tumor effect of SGLXD was evaluated in non-ovariectomized and ovariectomized athymic nude mice. The effect of SGLXD on enzymatic activity of aromatase and STS was examined using the dual-luciferase reporter (DLR) based on bioluminescent measurements. Aromatase and STS protein level were assessed using Western blot assay. SGLXD showed dose-dependent inhibitory effect on the proliferation of ZR-75-1 cells with IC50 value of 3.40 mg/mL. It also suppressed the stimulating effect on cell proliferation of testosterone and estrogen sulfates (E1S). Oral administration of 6 g/kg of SGLXD for 25 days resulted in a reduction in tumor volume in non-ovariectomized and ovariectomized nude mice. The bioluminescent measurements confirmed that SGLXD has a dual-inhibitory effect on the activity of aromatase and STS. Western blot assay demonstrated that the treatment of SGLXD resulted in a decrease in aromatase and STS protein levels both in vitro and in vivo. Our results suggested that SGLXD showed anti-tumor effect on breast cancer cells both in vitro and in vivo. The anti-tumor activity of SGLXD is related to inhibition of aromatase and STS via decreasing their expression. SGLXD may be considered as a novel treatment for ER positive breast cancer. Copyright © 2014 Elsevier

  13. Desmoid tumor following abdominally-based free flap breast reconstruction

    PubMed Central

    Oh, Christine; Hammoudeh, Ziyad S.

    2017-01-01

    Desmoid tumors are fibroblastic connective tissue tumors that most commonly develop within the anterior abdominal wall. The etiology of desmoid tumors has not been well defined; however, hereditary, hormonal, traumatic, and surgery-related causes have been implicated. Desmoid tumors are believed to arise from musculoaponeurotic structures. Development in the breast is very rare. Several reports of desmoid tumors arising in the vicinity of the fibrous capsule of a breast implant have been described, but to date, the authors are not aware of any published cases following autologous breast reconstruction. This report describes a desmoid tumor developing after a muscle-sparing free transverse rectus abdominis musculocutaneous (TRAM) flap for breast reconstruction and subsequent surgical management. PMID:28210557

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

    ClinicalTrials.gov

    2016-12-09

    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

  15. 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.

  16. Maximizing Immune Response to Carbohydrate Antigens on Breast Tumors

    DTIC Science & Technology

    2003-08-01

    antigens expressed on breast tumors. Towards this end we are developing peptide mimotopes of tumor associated carbohydrate antigens as they are T cell...dependent antigens. In our progress to date we have shown the 1) immunization with peptide mimotope activates a specific cellular response to a model murine...tumor cell line; 2) vaccination of mice with peptide eradicates established tumor; 3) Immunization with DNA format of the peptide suppresses tumor

  17. Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research.

    PubMed

    Alqaisi, Abeer; Chen, Li; Romond, Edward; Chambers, Mara; Stevens, Mark; Pasley, Grace; Awasthi, Mukta; Massarweh, Suleiman

    2014-11-01

    ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen

  18. Dormancy Signatures and Metastasis in Estrogen Receptor Positive and Negative Breast Cancer

    PubMed Central

    Kim, Ryung S.; Avivar-Valderas, Alvaro; Estrada, Yeriel; Bragado, Paloma; Sosa, Maria Soledad; Aguirre-Ghiso, Julio A.; Segall, Jeffrey E.

    2012-01-01

    Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines. PMID:22530051

  19. Tumor-to-breast volume ratio as measured on MRI: a possible predictor of breast-conserving surgery versus mastectomy.

    PubMed

    Faermann, Renata; Sperber, Fani; Schneebaum, Schlomo; Barsuk, Daphna

    2014-02-01

    The surgical approach to breast cancer changed dramatically in the past 20 years. The surgical objective today is to remove the tumor, ensuring negative margins and good cosmetic results, and preserving the breast when possible. Magnetic resonance imaging of the breast has become an essential imaging tool prior to surgery, diagnosing additional tumors and assessing tumor extent. Tumor-to-breast volume ratio, an important predictor of breast conservation, can be measured with MRI and may change the surgical decision. To measure the tumor-to-breast volume ratio using MRI in order to assess whether there is a correlation between this ratio and the type of surgery selected (breast-conserving or mastectomy). The volumes of the tumor and the breast and the tumor-to-breast volume ratio were retrospectively calculated using preoperative breast MRI in 76 patients who underwent breast-conserving surgery or mastectomy. Breast-conserving surgery (lumpectomy) was performed in 64 patients and mastectomy in 12. The average tumor-to-breast volume ratio was 0.06 (6%) in the lumpectomy group and 0.30 (30%) in the mastectomy group (P < 0.0001). The tumor-to-breast volume ratio correlated with the type of surgery. As measured on MRI, this ratio is an accurate means of determining the type of surgery best suited for a given patient. It is recommended that MRI-determined tumor-to-breast volume ratio become part of the surgical planning protocol for patients diagnosed with breast cancer.

  20. The Role of DNA Methyltransferase in the Progression of Breast Cancer of a Hormone Independent Phenotype

    DTIC Science & Technology

    1999-09-01

    suggesting that overexpression of DMT may be necessary for maintenance of aberrant methylation patterns. In examining primary breast tumor tissue , we found...unmethylated except for genes on the inactive X chromosome and some imprinted genes (Li, et al, 1993). In contrast, cancer cells often display anomalous...cell lines and primary tumors, but remains unmethylated in normal tissues and ER-positive breast cancer cell lines. Furthermore, treatment of the ER

  1. 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

    2015-02-27

    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.

  2. 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

  3. 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.

  4. Role of Fetuin-A in Breast Tumor Cell Growth

    DTIC Science & Technology

    2008-03-30

    0254 TITLE: Role of Fetuin -A in Breast Tumor Cell Growth PRINCIPAL INVESTIGATOR: Josiah Ochieng, Ph.D...Role of fetuin -A in Breast Tumor Cell Growth 5a. CONTRACT NUMBER W81XWH-07-1-0254 5b. GRANT NUMBER BC060744 5c. PROGRAM ELEMENT...ABSTRACT. In this report, we have described the breeding protocol we have followed aimed at knocking out the fetuin -A gene in PymT+ transgenic black C57

  5. Role of Fetuin-A in Breast Tumor Cell Growth

    DTIC Science & Technology

    2010-03-01

    AD_________________ Award Number: W81XWH-07-1-0254 TITLE: Role of Fetuin -A in Breast Tumor Cell...From - To) 31 MAR 2007 - 28 FEB 2010 4. TITLE AND SUBTITLE Role of fetuin -A in Breast Tumor Cell Growth 5a. CONTRACT NUMBER W81XWH-07-1-0254...reportable outcome of this task is that we have now removed doubts regarding the authenticity of fetuin -A as adhesion and growth signaling molecule. The

  6. Giant cell tumor of soft tissue arising in breast.

    PubMed

    May, Steve A; Deavers, Michael T; Resetkova, Erika; Johnson, Deborah; Albarracin, Constance T

    2007-10-01

    Primary giant cell tumor of soft tissue (GCT-ST) arising in breast is exceedingly rare. We report a case of a 60-year-old woman with a primary breast giant cell tumor that appeared histologically identical to giant cell tumor of bone and had a clinically malignant course. The patient presented with a cystic mass of the breast, suspected on imaging to be an organizing hematoma, possibly related to previous injury. Histopathological evaluation revealed a neoplasm composed of mononuclear cells admixed with osteoclast-like giant cells resembling giant cell tumor of bone. Immunohistochemical staining was positive for CD68, smooth muscle actin, and vimentin, but was negative for a panel of epithelial and additional muscle markers. These features were most consistent with GCT-ST, an uncommon neoplasm of low malignant potential. Despite aggressive surgical treatment achieving clear surgical margins, the patient expired with pulmonary metastases within a year of her initial presentation. This case demonstrates the difficulty of predicting clinical behavior of GCT-ST of breast on the basis of histological features and depth of tumor alone. To our knowledge, this is the first case report of a GCT-ST arising in the breast associated with a fatal outcome. The distinction of this entity from other more common primary breast tumors with giant cell morphology is also emphasized.

  7. 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.

  8. 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

  9. Phyllodes tumors of the breast: diagnosis, treatment and prognostic factors related to recurrence

    PubMed Central

    Zhou, Zhi-Rui; Wang, Chen-Chen; Yang, Zhao-Zhi

    2016-01-01

    Phyllodes tumors of the breast are rare tumor types that consist of 0.3–1.0% in all breast tumors. The naming and classification of breast phyllodes tumor have been debated for years. Based on the classification criteria modified by WHO in 2003, this review mainly introduced the clinicopathologic characteristics, pre-operational diagnosis and the treatment of breast phyllodes tumors, and also summarized the prognostic factors related to tumor recurrence. PMID:28066617

  10. Optically Measured Microvascular Blood Flow Contrast of Malignant Breast Tumors

    PubMed Central

    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

  11. Detection of cellular senescence within human invasive breast carcinomas distinguishes different breast tumor subtypes.

    PubMed

    Cotarelo, Cristina L; Schad, Arno; Kirkpatrick, Charles James; Sleeman, Jonathan P; Springer, Erik; Schmidt, Marcus; Thaler, Sonja

    2016-11-15

    Oncogene-induced senescence is thought to act as a barrier to tumorigenesis by arresting cells at risk of malignant transformation. Nevertheless, numerous findings suggest that senescent cells may conversely promote tumor progression through the development of the senescence-associated secretome they produce. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes due to different subsets of genetic and epigenetic abnormalities. As tumor initiation and progression of these breast cancer subtypes is triggered by diverse oncogenic stimuli, differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Many studies have addressed the role of senescence as a barrier to tumor progression using murine xenograft models. However, few investigations have been performed to elucidate the degree to which senescent tumor cells are present within untreated human tumors, and if present, whether these senescent tumor cells may play a role in disease progression. In the present study we analysed the appearance of senescent cells within invasive breast cancers. Detection of cellular senescence by the use of SAβ-galactosidase (SAβ-gal) staining within invasive breast carcinoms from 129 untreated patients revealed differences in the amount of SAβ-gal+ tumor cells between breast cancer subtypes. The highest percentages of SAβ-gal+ tumor cells were found in HER2-positive and luminal A breast carcinomas whereas triple negative tumors showed either little or no positivity.

  12. Detection of cellular senescence within human invasive breast carcinomas distinguishes different breast tumor subtypes

    PubMed Central

    Cotarelo, Cristina L.; Schad, Arno; Kirkpatrick, Charles James; Sleeman, Jonathan P.; Springer, Erik; Schmidt, Marcus; Thaler, Sonja

    2016-01-01

    Oncogene-induced senescence is thought to act as a barrier to tumorigenesis by arresting cells at risk of malignant transformation. Nevertheless, numerous findings suggest that senescent cells may conversely promote tumor progression through the development of the senescence-associated secretome they produce. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes due to different subsets of genetic and epigenetic abnormalities. As tumor initiation and progression of these breast cancer subtypes is triggered by diverse oncogenic stimuli, differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Many studies have addressed the role of senescence as a barrier to tumor progression using murine xenograft models. However, few investigations have been performed to elucidate the degree to which senescent tumor cells are present within untreated human tumors, and if present, whether these senescent tumor cells may play a role in disease progression. In the present study we analysed the appearance of senescent cells within invasive breast cancers. Detection of cellular senescence by the use of SAβ-galactosidase (SAβ-gal) staining within invasive breast carcinoms from 129 untreated patients revealed differences in the amount of SAβ-gal+ tumor cells between breast cancer subtypes. The highest percentages of SAβ-gal+ tumor cells were found in HER2-positive and luminal A breast carcinomas whereas triple negative tumors showed either little or no positivity. PMID:27713152

  13. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.

    PubMed

    Fröhlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar; Kronqvist, Pauliina; Kveiborg, Marie; Sehara-Fujisawa, Atsuko; Mercurio, Arthur M; Wewer, Ulla M

    2011-11-01

    Expression of ADAM12 is low in most normal tissues but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma, ADAM12 is almost exclusively located in tumor cells and, only rarely, seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.

  14. 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.

  15. Sex steroids in human brain tumors and breast cancer.

    PubMed

    von Schoultz, E; Bixo, M; Bäckström, T; Silfvenius, H; Wilking, N; Henriksson, R

    1990-02-15

    The concentrations of three sex steroids, estradiol, progesterone and testosterone, were analyzed by radioimmunoassay after celite chromatography in brain tumor and breast cancer tissues. The concentrations in malignant gliomas and breast cancers showed interindividual variations, especially evident with regard to estradiol. High estradiol concentrations were recorded in two patients with malignant astrocytoma. The concentrations of 1.00 pg/mg and 3.32 pg/mg were 10 to 30 times as high as in normal female brain. In five of ten astrocytomas the estradiol concentration was higher than the lowest breast cancer value. The distribution of progesterone seemed more even, and the level was significantly lower in brain tumors and breast cancers as compared with female brain, perhaps indicating an increased metabolism. Testosterone levels were somewhat higher in brain tumors, as compared with breast cancers, but not different from values in brain tissue. There were no significant age or sex correlation or differences in the concentrations of steroids in the brain tumors. The results suggest that manipulation of sex steroid metabolism in malignant brain tumors can be of beneficial therapeutic value as has been shown for breast cancer and prostatic carcinoma.

  16. Imaging features of carcinoid tumors metastatic to the breast

    PubMed Central

    Jones, Katie N.; Dilaveri, Christina A.; Perry, Kyle; Reynolds, Carol

    2011-01-01

    Abstract The objective of this study was to describe the imaging findings of carcinoid tumors metastatic to the breast, with pathologic and clinical correlations. We searched our surgical database for cases of pathologically proven carcinoid tumors metastatic to the breast from October 1, 2000, to May 31, 2010. Of the approximate 10,000 breast biopsies identified, 7000 had malignant findings. Ten cases of metastatic carcinoid (0.1% of all malignancies), all with imaging studies available for review, were included in the study. All patients were women and had their primary carcinoid in the gastrointestinal tract (n=9) or lung (n = 1). One patient presented with a palpable breast mass and no history of carcinoid tumor; an ileal carcinoid was discovered after the pathologic diagnosis of metastatic carcinoid was established. In the breast, tumors presented as solitary lesions in half the cases. Metastases to the breast typically presented as circumscribed masses mammographically and as hypoechoic circumscribed masses ultrasonographically; some showed increased through-transmission and increased vascularity with color Doppler evaluation. Five patients had octreotide scans; of these, 4 had increased focal activity in the region of metastasis within the breast. Six patients underwent computed tomography. Without contrast, nodular masses were observed; with contrast, the masses showed rapid enhancement during arterial phase imaging. Magnetic resonance imaging (n = 4) also showed rapid enhancement and washout kinetics after contrast administration. Recognition of carcinoid metastases to the breast in patients with known or occult primary carcinoid tumors is important to avoid unnecessary treatment for primary breast cancer. PMID:21771708

  17. A model of tumor architecture and spatial interactions with tumor microenvironment in breast carcinoma

    NASA Astrophysics Data System (ADS)

    Ben Cheikh, Bassem; Bor-Angelier, Catherine; Racoceanu, Daniel

    2017-03-01

    Breast carcinomas are cancers that arise from the epithelial cells of the breast, which are the cells that line the lobules and the lactiferous ducts. Breast carcinoma is the most common type of breast cancer and can be divided into different subtypes based on architectural features and growth patterns, recognized during a histopathological examination. Tumor microenvironment (TME) is the cellular environment in which tumor cells develop. Being composed of various cell types having different biological roles, TME is recognized as playing an important role in the progression of the disease. The architectural heterogeneity in breast carcinomas and the spatial interactions with TME are, to date, not well understood. Developing a spatial model of tumor architecture and spatial interactions with TME can advance our understanding of tumor heterogeneity. Furthermore, generating histological synthetic datasets can contribute to validating, and comparing analytical methods that are used in digital pathology. In this work, we propose a modeling method that applies to different breast carcinoma subtypes and TME spatial distributions based on mathematical morphology. The model is based on a few morphological parameters that give access to a large spectrum of breast tumor architectures and are able to differentiate in-situ ductal carcinomas (DCIS) and histological subtypes of invasive carcinomas such as ductal (IDC) and lobular carcinoma (ILC). In addition, a part of the parameters of the model controls the spatial distribution of TME relative to the tumor. The validation of the model has been performed by comparing morphological features between real and simulated images.

  18. Distinct tumor protein p53 mutants in breast cancer subgroups.

    PubMed

    Dumay, Anne; Feugeas, Jean-Paul; Wittmer, Evelyne; Lehmann-Che, Jacqueline; Bertheau, Philippe; Espié, Marc; Plassa, Louis-François; Cottu, Paul; Marty, Michel; André, Fabrice; Sotiriou, Christos; Pusztai, Lajos; de Thé, Hugues

    2013-03-01

    Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes. Copyright © 2012 UICC.

  19. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.

    PubMed

    Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat

    2011-05-01

    Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.

  20. Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness.

    PubMed

    Welch, H Gilbert; Prorok, Philip C; O'Malley, A James; Kramer, Barnett S

    2016-10-13

    The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time. We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002). After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors

  1. Current Status of Autologous Breast Tumor Cell-based Vaccines

    PubMed Central

    Kurtz, Samantha L.; Ravindranathan, Sruthi; Zaharoff, David A.

    2015-01-01

    Summary Approximately 9 of 10 breast cancer-related deaths are attributable to metastasis. Yet, less than 4% of breast cancer patients are initially diagnosed with metastatic cancer. Therefore, the majority of breast cancer-related deaths are due to recurrence and progression of nonmetastatic disease. There is tremendous clinical opportunity for novel adjuvant strategies, such as immunotherapies, that have the potential to prevent progressive recurrences. In particular, autologous tumor cell-based vaccines can train a patient's immune system to recognize and eliminate occult disease. Autologous tumor cell-based vaccines have several advantages including safety, multivalency and patient specificity. Furthermore, because lumpectomy or mastectomy is indicated for the vast majority of breast cancer patients, resected tumors offer a readily available, patient-specific source of tumor antigen. Disadvantages of autologous tumor cell-based vaccines include poor immunogenicity and production inconsistencies. This review summarizes recent progress in the development of autologous breast tumor vaccines and offers insight for overcoming existing limitations. PMID:25308888

  2. Minimal residual disease and circulating tumor cells in breast cancer

    PubMed Central

    2011-01-01

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis. PMID:22078011

  3. Minimal residual disease and circulating tumor cells in breast cancer.

    PubMed

    Ignatiadis, Michail; Reinholz, Monica

    2011-10-25

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis.

  4. Role of the Tumor Microenvironment in Breast Cancer.

    PubMed

    Soysal, Savas D; Tzankov, Alexandar; Muenst, Simone E

    2015-09-01

    In recent years, it has been shown that breast cancer consists not only of neoplastic cells, but also of significant alterations in the surrounding stroma or tumor microenvironment. These alterations are now recognized as a critical element for breast cancer development and progression, as well as potential therapeutic targets. Various components of the breast cancer microenvironment, such as suppressive immune cells, soluble factors and altered extracellular matrix, act together to impede effective antitumor immunity and promote breast cancer progression and metastasis. Stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, some of which are prognostic of clinical outcome. Several new therapies targeting stromal components are in development or undergoing clinical trials. We focus herein on the composition of the breast cancer microenvironment and concomitant molecular alterations, the specific interplay between various cell types and cancer cells, and the clinical implications of these findings. © 2015 S. Karger AG, Basel.

  5. A visual analytics system for breast tumor evaluation.

    PubMed

    Petushi, Sokol; Marker, Jeffrey; Zhang, Jasper; Zhu, Weizhong; Breen, David; Chen, Chaomei; Lin, Xia; Garcia, Fernando U

    2008-10-01

    To develop a system for the interactive exploration and examination of histologically derived data that is associated with breast tumors and may be used to evaluate the histologic grade of the tumor. The system integrates pathologist-generated prognostic data with 2-dimensional (2-D) image analysis data, 2-D digital tissue cross-sections and annotations, 3-dimensional (3-D) tumor reconstructions and volumetric analysis, 3D spatial tumor display and recorded prognostic information from available cases in the Drexel University College of Medicine tumor databank. The system consists of 3 components: (1) a user interface for applying 2-D image processing, segmentation and annotation to a digitized histology slide, (2) a distance field interpolation method for contour-based 3D reconstruction of breast tumors and volumetric model analysis routines and (3) a Web-based database management interface for interactive data browsing and searching and multimodality visualization. The system has been implemented and deployed with data from 36 breast cancer cases, 7 of which have been reconstructed in 3-D. Interactive visual analytics technology may be used to create an effective breast tumor evaluation system.

  6. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior

    PubMed Central

    Banin Hirata, Bruna Karina; Oda, Julie Massayo Maeda; Losi Guembarovski, Roberta; Ariza, Carolina Batista; de Oliveira, Carlos Eduardo Coral; Watanabe, Maria Angelica Ehara

    2014-01-01

    Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity. PMID:24591761

  7. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity

    PubMed Central

    Zhang, Huang-Ge; Kim, Helen; Liu, Cunren; Yu, Shaohua; Wang, Jianhua; Grizzle, William E.; Kimberly, Robert P.; Barnes, Stephen

    2007-01-01

    An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties curcumin. PMID:17555831

  8. 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

  9. Rare Malignant Tumors of the Breast.

    PubMed

    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.

  10. Global MicroRNA Expression Profiling Identifies MiR-210 Associated with Tumor Proliferation, Invasion and Poor Clinical Outcome in Breast Cancer

    PubMed Central

    Rothé, Françoise; Ignatiadis, Michail; Chaboteaux, Carole; Haibe-Kains, Benjamin; Kheddoumi, Naïma; Majjaj, Samira; Badran, Bassam; Fayyad-Kazan, Hussein; Desmedt, Christine; Harris, Adrian L.; Piccart, Martine; Sotiriou, Christos

    2011-01-01

    Purpose Aberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients. Experimental Design Global miRNA expression profiling using microarray technology was conducted in 56 systemically untreated BC patients who had corresponding mRNA expression profiles available. Results were further confirmed using qRT-PCR in an independent dataset of 89 ER-positive BC patients homogeneously treated with tamoxifen only. MiR-210 functional analyses were performed in MCF7 and MDA-MB-231 BC cell lines using lentiviral transduction. Results Estrogen receptor (ER) status, tumor grade and our previously developed gene expression grade index (GGI) were associated with distinct miRNA profiles. Several miRNAs were found to be clinically relevant, including miR-210, its expression being associated with tumor proliferation and differentiation. Furthermore, miR-210 was associated with poor clinical outcome in ER-positive, tamoxifen-treated BC patients. Interestingly, the prognostic performance of miR-210 was similar to several reported multi-gene signatures, highlighting its important role in BC differentiation and tumor progression. Functional analyses in BC cell lines revealed that miR-210 is involved in cell proliferation, migration and invasion. Conclusions This integrated analysis combining miRNA and mRNA expression demonstrates that miRNA expression provides additional biological information beyond mRNA expression. Expression of miR-210 is linked to tumor proliferation and appears to be a strong potential biomarker of clinical outcome in BC. PMID:21738599

  11. 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.

  12. Role of Fetuin-A in Breast Tumor Cell Growth

    DTIC Science & Technology

    2009-03-01

    Growth PRINCIPAL INVESTIGATOR: Josiah Ochieng, Ph.D. CONTRACTING ORGANIZATION: Meharry Medical College Nashville, TN 37208...COVERED (From - To) 4. TITLE AND SUBTITLE Role of fetuin-A in Breast Tumor Cell Growth 5a. CONTRACT NUMBER W81XWH-07-1-0254 5b. GRANT NUMBER...hypothesis of this grant is that fetuin-A is a major serum derived growth factor for breast carcinoma cells and creates a favorable environment for the

  13. Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer.

    PubMed

    Smeets, Ann; Ryckx, Andries; Belmans, Ann; Wildiers, Hans; Neven, Patrick; Floris, Giuseppe; Schöffski, Patrick; Christiaens, Marie-Rose

    2013-01-01

    The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases. Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases. We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models. Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated. According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.

  14. New Approaches for Early Detection of Breast Tumor Invasion or Progression

    DTIC Science & Technology

    2005-11-01

    cell clusters of in situ breast tumors. Breast Cancer Res Treat 89:199-208, 2005. 15. Man YG, Fu SW, Pinzone JJ, Schwartz AM, Simmens SJ, Berg PE... Pinzone JJ, Man YG. BP1 expression correlates with breast tumor aggreesiveness. Platform presentation at the 26th San Antonio Breast Cancer...137: 282, 2004 43. Berg P, Fu SW, Pinzone JJ, Man YG. The Expression of BP1, a homeotic protein, increases with breast tumor progression

  15. Optical assessment of tumor resection margins in the breast

    PubMed Central

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

    2011-01-01

    Breast conserving surgery, in which the breast tumor and surrounding normal tissue are removed, is the primary mode of treatment for invasive and in situ carcinomas of the breast, conditions that affect nearly 200,000 women annually. Of these nearly 200,000 patients who undergo this surgical procedure, between 20–70% of them may undergo additional surgeries to remove tumor that was left behind in the first surgery, due to the lack of intra-operative tools which can detect whether the boundaries of the excised specimens are free from residual cancer. Optical techniques have many attractive attributes which may make them useful tools for intra-operative assessment of breast tumor resection margins. In this manuscript, we discuss clinical design criteria for intra-operative breast tumor margin assessment, and review optical techniques appied to this problem. In addition, we report on the development and clinical testing of quantitative diffuse reflectance imaging (Q-DRI) as a potential solution to this clinical need. Q-DRI is a spectral imaging tool which has been applied to 56 resection margins in 48 patients at Duke University Medical Center. Clear sources of contrast between cancerous and cancer-free resection margins were identified with the device, and resulted in an overall accuracy of 75% in detecting positive margins. PMID:21544237

  16. 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

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

    PubMed

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

    2015-06-01

    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. DNA methylation was evaluated at 1,287 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 (CBCS). Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four 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 (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific. Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases. Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. ©2015 American Association for Cancer Research.

  18. Quantitative Analysis of Mitochondrial DNA 4977-bp Deletion in Sporadic Breast Cancer and Benign Breast Tumors

    PubMed Central

    Ye, Chuanzhong; Shu, Xiao-Ou; Wen, Wanqing; Pierce, Larry; Courtney, Regina; Gao, Yu-Tang; Zheng, Wei; Cai, Qiuyin

    2013-01-01

    The mitochondrial DNA (mtDNA) 4977-bp deletion (ΔmtDNA4977 mutation) is one of the most frequently observed mtDNA mutations in human tissues, and may play a role in carcinogenesis. Only a few studies have evaluated ΔmtDNA4977 mutation in breast cancer tissue, and the findings have been inconsistent, which may be due to methodological differences. In this study, we developed a quantitative real-time PCR assay to assess the level of the ΔmtDNA4977 mutation in tumor tissue samples from 55 primary breast cancer patients and 21 patients with benign breast disease (BBD). The ΔmtDNA4977 mutation was detected in all of the samples with levels varying from 0.000149% to 7.0%. The ΔmtDNA4977 mutation levels were lower in tumor tissues than in adjacent normal tissues in both breast cancer and BBD subjects. The differences, however, were not statistically significant. No significant difference between breast cancer and BBD patients was found in the ΔmtDNA4977 mutation levels of tumor tissues and adjacent normal tissues. The ΔmtDNA4977 mutation levels were not significantly associated with clinicopathological characteristics (age, histology, tumor stage, and ER/PR status) in breast cancer or BBD patients. These results do not support the notion that the mitochondrial DNA 4977-bp deletion plays a major role in breast carcinogenesis. PMID:17541740

  19. The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

    PubMed Central

    Dore-Savard, Louis; Lee, Esak; Kakkad, Samata; Popel, Aleksander S.; Bhujwalla, Zaver M.

    2016-01-01

    The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression. Angiogenesis-related factors were characterized in the TIF and plasma, to understand the relationship between the TIF and plasma secretomes. Clear differences were observed between the TIF and plasma angiogenic secretomes in triple negative MDA-MB-231 breast cancer xenografts compared to ER-positive MCF-7 xenografts with or without VEGF overexpression that provide new insights into TIF components and the role of VEGF in modifying the angiogenic secretome. PMID:27995973

  20. Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment.

    PubMed

    Li, Z; Xiao, J; Wu, X; Li, W; Yang, Z; Xie, J; Xu, L; Cai, X; Lin, Z; Guo, W; Luo, J; Liu, M

    2012-09-01

    Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called 'vicious cycle' that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.

  1. 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

  2. Noncontact diffuse correlation tomography of human breast tumor

    PubMed Central

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

    2015-01-01

    Abstract. Our first step to adapt our recently developed noncontact diffuse correlation tomography (ncDCT) system for three-dimensional (3-D) imaging of blood flow distribution in human breast tumors is reported. A commercial 3-D camera was used to obtain breast surface geometry, which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the mesh surface and the measured boundary data were combined with a finite element framework for 3-D image reconstruction of blood flow distribution. This technique was tested in computer simulations and in vivo human breasts with low-grade carcinoma. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor is within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor blood flow contrasts. In vivo imaging results from two breast carcinomas show higher average blood flow contrasts (5.9- and 10.9-fold) in the tumor regions compared to the surrounding tissues, which are comparable with previous findings using diffuse correlation spectroscopy. The ncDCT system has the potential to image blood flow distributions in soft and vulnerable tissues without distorting tissue hemodynamics. PMID:26259706

  3. 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.

  4. Noncontact diffuse correlation tomography of human breast tumor.

    PubMed

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

    2015-08-01

    Our first step to adapt our recently developed noncontact diffuse correlation tomography (ncDCT) system for three-dimensional (3-D) imaging of blood flow distribution in human breast tumors is reported. A commercial 3-D camera was used to obtain breast surface geometry, which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the mesh surface and the measured boundary data were combined with a finite element framework for 3-D image reconstruction of blood flow distribution. This technique was tested in computer simulations and in vivo human breasts with low-grade carcinoma. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor is within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor blood flow contrasts. In vivo imaging results from two breast carcinomas show higher average blood flow contrasts (5.9- and 10.9-fold) in the tumor regions compared to the surrounding tissues, which are comparable with previous findings using diffuse correlation spectroscopy. The ncDCT system has the potential to image blood flow distributions in soft and vulnerable tissues without distorting tissue hemodynamics

  5. Tumor microenvironment-mediated chemoresistance in breast cancer.

    PubMed

    Velaei, Kobra; Samadi, Nasser; Barazvan, Balal; Soleimani Rad, Jafar

    2016-12-01

    Therapy resistance or tumor relapse in cancer is common. Tumors develop resistance to chemotherapeutic through a variety of mechanisms, with tumor microenvironment (TM) serving pivotal roles. Using breast cancer as a paradigm, we propose that responses of cancer cells to drugs are not exclusively determined by their intrinsic characteristics but are also controlled by deriving signals from TM. Affected microenvironment by chemotherapy is an avenue to promote phenotype which tends to resist on to be ruined. Therefore, exclusively targeting cancer cells does not demolish tumor recurrence after chemotherapy. Regardless of tumor-microenvironment pathways and their profound influence on the responsiveness of treatment, diversity of molecular properties of breast cancer also behave differently in terms of response to chemotherapy. And also it is assumed that there is cross-talk between phenotypic diversity and TM. Collectively, raising complex signal from TM in chemotherapy condition often encourages cancer cells are not killed but strengthen. Here, we summarized how TM modifies responses to chemotherapy in breast cancer. We also discussed successful treatment strategies have been considered TM in breast cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Unusual aggressive breast cancer: metastatic malignant phyllodes tumor.

    PubMed

    Singer, Adam; Tresley, Jonathan; Velazquez-Vega, Jose; Yepes, Monica

    2013-02-01

    For the year of 2012, it has been estimated that breast cancer will account for the greatest number of newly diagnosed cancers and the second highest proportion of cancer related deaths among women. Breast cancer, while often lumped together as one disease, represents a diverse group of malignancies with different imaging findings, histological appearances and behavior. While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as the phyllodes tumor may arise from mesenchymal tissue. Compared to the breast adenocarcinoma, the phyllodes tumor tends to affect a younger population, follows a different clinical course, is associated with different imaging and histological findings and is managed distinctively. There may be difficulty in differentiating the phyllodes tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis with proper surgical management can often cure non-metastatic phyllodes tumors. However, in rare cases where metastasis occurs, prognosis tends to be poor. This report describes the presentation, imaging findings and management of a metastatic malignant phyllodes tumor.

  7. Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study

    PubMed Central

    O’Brien, Katie M.; Cole, Stephen R.; Tse, Chiu-Kit; Perou, Charles M.; Carey, Lisa A.; Foulkes, William D.; Dressler, Lynn G.; Geradts, Joseph; Millikan, Robert C.

    2010-01-01

    Purpose Previous research identified differences in breast cancer-specific mortality across four "intrinsic" tumor subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 positive/estrogen receptor negative (HER2+/ER−). Experimental Design We used immunohistochemical markers to subtype 1149 invasive breast cancer patients (518 African American, 631 white) in the Carolina Breast Cancer Study, a population-based study of women diagnosed with breast cancer. Vital status was determined through 2006 using the National Death Index, with median follow-up of 9 years. Results Cancer subtypes luminal A, luminal B, basal-like and HER2+/ER- were distributed as 64%, 11%, 11% and 5% for whites, and 48%, 8%, 22% and 7% for African Americans, respectively. Breast cancer mortality was higher for patients with HER2+/ER- and basal-like breast cancer compared to luminal A and B. African Americans had higher breast-cancer specific mortality than whites, but the effect of race was statistically significant only among women with luminal A breast cancer. However, when compared to the luminal A subtype within racial categories, mortality for patients with basal-like breast cancer was higher among whites (HR=2.0, 95% CI: 1.2, 3.4) than African Americans (HR=1.5, 95% CI: 1.0, 2.4), with the strongest effect seen in postmenopausal white women (HR=3.9, 95% CI: 1.5, 10.0). Conclusions Our results confirm the association of basal-like breast cancer with poor prognosis, and suggest that basal-like breast cancer is not an inherently more aggressive disease in African American women compared to whites. Additional analyses are needed in populations with known treatment profiles to understand the role of tumor subtypes and race in breast cancer mortality, and in particular our finding that among women with luminal A breast cancer, African Americans have higher mortality than whites. PMID:21169259

  8. Breast Cancer Stem Cells in Antiestrogen Resistance

    DTIC Science & Technology

    2013-08-01

    SOW). We have successfully used the Lentivirus-based ER-α36 shRNA system to express ER-α36 shRNA in MCF7/HER-2/18 cells and established a stable...variant, ER-α36, in resistance of breast cancer stem/progenitor cells to antiestrogens. In the past two years, we have accomplished most of the works...such as tamoxifen provided a successful treatment for ER-positive breast cancer for the past two decades. However, most breast tumors are eventually

  9. RACE-ASSOCIATED BIOLOGICAL DIFFERENCES AMONG LUMINAL A BREAST TUMORS

    PubMed Central

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

    2015-01-01

    Purpose 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 outcomes Luminal A breast cancers. These differences may reflect treatment or health care access issues, inherent biological differences, or both. Methods 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 next evaluated for associations with survival. Finally, expression of race- and survival-associated genes was evaluated in normal tissue of AA and CAU women. Results 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 vs. CAU women’s normal tissue. Conclusions 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 even precede malignancy. PMID:26109344

  10. PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression.

    PubMed

    Panet, François; Couture, Frédéric; Kwiatkowska, Anna; Desjardins, Roxane; Guérin, Brigitte; Day, Robert

    2017-08-01

    Breast cancer is the most frequent and deadly malignancy in women worldwide. Despite national screening programs combined with new treatments relapse rate remain high and new therapies are needed. From previous work, we identified PACE4, a member of the proprotein convertase (PCs) family of endoproteases, as a novel therapeutic target in prostate cancer. In the present study we asked the question if PACE4 could also be a potential target in breast cancer. In clinical samples of breast adenocarcinoma, we observed a specific overexpression of PACE4 in the estrogen-receptor (ER) positive subtype. We therefore looked for a breast cancer cell line model which would be representative and thus focused on the ZR-75-1 since it both expresses PACE4 and is estrogen-receptor positive. We compared stable knockdowns of furin, PACE4 and PC7 in the estrogen-receptor-positive cell line ZR-75-1 to evaluate their respective contribution to cell growth and tumor progression. PACE4 was the only PC displaying an impact on cell growth. A PACE4 peptide-based inhibitor (C23) was tested and shown to decrease proliferation of ZR-75-1 cells in cell based assays. C23 also had potent effects of tumor progression in vivo on xenografts of the ZR-75-1 cell line in athymic nude mice. Thus, PACE4-silencing and systemic administration of a PACE4 inhibitor resulted in hindered tumor progression with reduction in proliferative indices and increased cell quiescence assessed with biomarkers. Our results suggest that PACE4 is a promising target for estrogen-receptor-positive breast cancer. Copyright © 2017 Elsevier GmbH. All rights reserved.

  11. Assessing Vascular Oxygen Dynamics for Breast Tumor Prognosis: Comparison Between MR BOLD and Near Infrared Method

    DTIC Science & Technology

    2005-09-01

    treat- ments, such as chemotherapy and radiotherapy (37). In summary, changes in breast tumor temperature and vascular oxygenation have been... Breast Tumor Prognosis: Comparison Between MR BOLD and Near Infrared Method PRINCIPAL INVESTIGATOR: Hanli Liu, Ph.D...CONTRACT NUMBER Assessing Vascular Oxygen Dynamics for Breast Tumor Prognosis: Comparison Between MR BOLD and Near Infrared Method

  12. Microwave detection of breast tumors: comparison of skin subtraction algorithms

    NASA Astrophysics Data System (ADS)

    Fear, Elise C.; Stuchly, Maria A.

    2000-07-01

    Early detection of breast cancer is an important part of effective treatment. Microwave detection of breast cancer is of interest due to the contrast in dielectric properties of normal and malignant breast tissues. We are investigating a confocal microwave imaging system that adapts ideas from ground penetrating radar to breast cancer detection. In the proposed system, the patient lies prone with the breast extending through a hole in the examining table and encircled by an array of antennas. The breast is illuminated sequentially by each antenna with an ultrawideband signal, and the returns are recorded at the same antenna. Because the antennas are offset from the breast, the dominant component of the recorded returns is the reflection from the thin layer of breast skin. Two methods of reducing this reflection are compared, namely approximation of the signal with two time shifted, scaled and summed returns from a cylinder of skin, and subtraction of the mean of the set of aligned returns. Both approaches provide effective decrease of the skin signal, allowing for tumor detection.

  13. Neoadjuvant Systemic Therapy in Breast Cancer: Association of Contrast-enhanced MR Imaging Findings, Diffusion-weighted Imaging Findings, and Tumor Subtype with Tumor Response.

    PubMed

    Santamaría, Gorane; Bargalló, Xavier; Fernández, Pedro Luis; Farrús, Blanca; Caparrós, Xavier; Velasco, Martin

    2017-06-01

    Purpose To investigate the performance of tumor subtype and various magnetic resonance (MR) imaging parameters in the assessment of tumor response to neoadjuvant systemic therapy (NST) in patients with breast cancer and to outline a model of pathologic response, considering pathologic complete response (pCR) as the complete absence of any residual invasive cancer or ductal carcinoma in situ (DCIS). Materials and Methods This was an institutional review board-approved retrospective study, with waiver of the need to obtain informed consent. From November 2009 to December 2014, 111 patients with histopathologically confirmed invasive breast cancer who were undergoing NST were included (mean age, 54 years; range, 27-84 years). Breast MR imaging was performed before and after treatment. Presence of late enhancement was assessed. Apparent diffusion coefficients (ADCs) were obtained by using two different methods. ADC ratio (mean posttreatment ADC/mean pretreatment ADC) was calculated. pCR was defined as absence of any residual invasive cancer or DCIS. Multivariate regression analysis and receiver operating characteristic analysis were performed. Results According to their immunohistochemical (IHC) profile, tumors were classified as human epidermal growth factor receptor 2 (HER2) positive (n = 51), estrogen receptor (ER) positive/HER2 negative (n = 40), and triple negative (n = 20). pCR was achieved in 19% (21 of 111) of cases; 86% of them were triple-negative or HER2-positive subtypes. Absence of late enhancement at posttreatment MR imaging was significantly associated with pCR (area under the curve [AUC], 0.85). Mean ADC ratio significantly increased when pCR was achieved (P < .001). A κ value of 0.479 was found for late enhancement (P < .001), and the intraclass correlation coefficient for ADCs was 0.788 (P < .001). Good correlation of ADCs obtained with the single-value method and those obtained with the mean-value methods was observed. The model combining the IHC

  14. Breast tumor classification via single-frequency microwave imaging

    NASA Astrophysics Data System (ADS)

    Do, Cuong M.; Bansal, Rajeev

    2013-05-01

    We propose a novel method for the classification of breast tumors (malignant versus benign) based on principal component analysis (PCA) following single-frequency microwave imaging. For initial evaluation, a simplified model of the biological tissue was developed in a frequency-domain finite-element framework. The model incorporated various combinations of dielectric constant and conductivity. A double-level classification scheme allows classifying a tumor with high accuracy.

  15. PET Radiotracers for Imaging the Proliferation Status of Breast Tumors

    DTIC Science & Technology

    2004-12-01

    that are antagonists of the dopamine D3 protein coupled receptor protein superfamily. Based receptor.t ’ 2 This interest was largely generated by the...receptor- based biomarker of of proliferation in breast tumor cells growing both in vitro and in vivo. During the second year of the three-year IDEA project...nucleoside- based approach that has been hypothesized to measure the proliferation in solid tumors. These studies were funded in part through the NIH grant CA1

  16. High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype.

    PubMed

    Dennison, Jennifer B; Shahmoradgoli, Maria; Liu, Wenbin; Ju, Zhenlin; Meric-Bernstam, Funda; Perou, Charles M; Sahin, Aysegul A; Welm, Alana; Oesterreich, Steffi; Sikora, Matthew J; Brown, Robert E; Mills, Gordon B

    2016-10-15

    The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior. Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging. A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05). A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers. Clin Cancer Res; 22(20); 5068-78. ©2016 AACR. ©2016 American Association for Cancer Research.

  17. Hormones and progeny of breast tumor cells.

    PubMed

    Schneider, H P G; Böcker, W

    2006-04-01

    The rudimentary human glandular breast, with the approach of puberty, starts to grow both at glandular and stromal sites. Full differentiation is a gradual process and takes many years, and is only fully attained by pregnancy. The risk of breast cancer is inversely related to parity. Women during adolescence have the highest susceptibility to breast cancer development. This appears to be the period when the mammary gland has the highest number of stem cells. Stem cells may represent important targets for transformational events. Immunohistochemistry allows for identification of the lineage-specific precursor glandular and myoepithelial cells and their differentiated progeny. Both estrogen receptor subtypes are found in epithelial cells of alveoli and ducts as well as in stromal cells. Immunophenotypia of benign proliferative breast disease favors a fundamentally different epithelial composition from that of most malignant epithelial proliferations such as atypical ductal hyperplasia, ductal carcinoma in situ, lobular neoplasia and invasive breast carcinoma. Immunophenotypical characterization of these lesions assists in distinguishing benign from malignant disease. Based on the observation of bilateral risks and frequent multifocality with atypical ductal hyperplasia, atypical lobular hyperplasia and lobular carcinoma in situ, it is suggested that these may represent risk factors as well as precursors. One should, however, realize that ductal as well as lobular premalignant breast lesions ultimately arise from stem cells in the terminal duct lobular units. Estrogen receptor-beta (ERbeta)-positive and ERalpha-negative expression characterizes the highest levels of proliferative cancer cell activity. Point mutations and alterations of co-activators and co-repressors will also determine hormone sensitivity. There is evidence for different genetic pathways in the development of ductal carcinoma in situ and lobular carcinoma in situ. While they share recurrent 16q

  18. 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

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

    PubMed

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

    2014-12-16

    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.

  20. Genes responsive to both oxidant stress and loss of estrogen receptor function identify a poor prognosis group of estrogen receptor positive primary breast cancers.

    PubMed

    Yau, Christina; Benz, Christopher C

    2008-01-01

    Oxidative stress can modify estrogen receptor (ER) structure and function, including induction of progesterone receptor (PR), altering the biology and clinical behavior of endocrine responsive (ER-positive) breast cancer. To investigate the impact of oxidative stress on estrogen/ER-regulated gene expression, RNA was extracted from ER-positive/PR-positive MCF7 breast cancer cells after 72 hours of estrogen deprivation, small-interfering RNA knockdown of ER-alpha, short-term (8 hours) exposure to various oxidant stresses (diamide, hydrogen peroxide, and menadione), or simultaneous ER-alpha knockdown and oxidant stress. RNA samples were analyzed by high-throughput expression microarray (Affymetrix), and significance analysis of microarrays was used to define gene signatures responsive to estrogen/ER regulation and oxidative stress. To explore the association of these signatures with breast cancer biology, microarray data were analyzed from 394 ER-positive primary human breast cancers pooled from three independent studies. In particular, an oxidant-sensitive estrogen/ER-responsive gene signature (Ox-E/ER) was correlated with breast cancer clinical parameters and disease-specific patient survival (DSS). From 891 estrogen/ER-regulated probes, a core set of 75 probes (62 unique genes) responsive to all three oxidants were selected (Ox-E/ER signature). Ingenuity pathway analysis of this signature highlighted networks involved in development, cancer, and cell motility, with intersecting nodes at growth factors (platelet-derived growth factor-BB, transforming growth factor-beta), a proinflammatory cytokine (tumor necrosis factor), and matrix metalloproteinase-2. Evaluation of the 394 ER-positive primary breast cancers demonstrated that Ox-E/ER index values correlated negatively with PR mRNA levels (rp = -0.2; P = 0.00011) and positively with tumor grade (rp = 0.2; P = 9.741 x e-5), and were significantly higher in ER-positive/PR-negative versus ER-positive/PR-positive breast

  1. Genomic alterations associated with early stages of breast tumor metastasis.

    PubMed

    Ellsworth, Rachel E; Ellsworth, Darrell L; Patney, Heather L; Deyarmin, Brenda; Hooke, Jeffrey A; Love, Brad; Shriver, Craig D

    2008-07-01

    Molecular studies suggest that acquisition of metastatic potential occurs early in the development of breast cancer; mechanisms by which cells disseminate from the primary carcinomas and successfully colonize foreign tissues are, however, largely unknown. Thus, we examined levels and patterns of chromosomal alterations in primary breast tumors from node-negative (n = 114) and node-positive (n = 115) patients to determine whether specific genomic changes are associated with tumor metastasis. Fifty-two genetic markers representing 26 chromosomal regions commonly altered in breast cancer were examined in laser microdissected tumor samples to assess levels and patterns of allelic imbalance (AI). Real time-PCR (RT-PCR) was performed to determine expression levels of candidate genes. Data was analyzed using exact unconditional and Student's t-tests with significance values of P < 0.05 and P < 0.002 used for the clinicopathological and genomic analyses, respectively. Overall levels of AI in primary breast tumors from node-negative (20.8%) and node-positive (21.9%) patients did not differ significantly (P = 0.291). When data were examined by chromosomal region, only chromosome 8q24 showed significantly higher levels (P < 0.0005) of AI in node-positive primary tumors (23%) versus node-negative samples (6%). c-MYC showed significantly higher levels of gene expression in primary breast tumors from patients with lymph node metastasis. Higher frequencies of AI at chromosome 8q24 in patients with positive lymph nodes suggest that genetic changes in this region are important to the process of metastasis. Because overexpression of c-MYC has been associated with cellular dissemination as well as development of the premetastatic niche, alterations of the 8q24 region, including c-MYC, may be key determinants in the development of lymph node metastasis.

  2. 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

  3. Tumor tissue protein signatures reflect histological grade of breast cancer

    PubMed Central

    Skoog, Petter; Ohlsson, Mattias; Fernö, Mårten; Rydén, Lisa; Borrebaeck, Carl A. K.

    2017-01-01

    Histological grade is one of the most commonly used prognostic factors for patients diagnosed with breast cancer. However, conventional grading has proven technically challenging, and up to 60% of the tumors are classified as histological grade 2, which represents a heterogeneous cohort less informative for clinical decision making. In an attempt to study and extend the molecular puzzle of histologically graded breast cancer, we have in this pilot project searched for additional protein biomarkers in a new space of the proteome. To this end, we have for the first time performed protein expression profiling of breast cancer tumor tissue, using recombinant antibody microarrays, targeting mainly immunoregulatory proteins. Thus, we have explored the immune system as a disease-specific sensor (clinical immunoproteomics). Uniquely, the results showed that several biologically relevant proteins reflecting histological grade could be delineated. In more detail, the tentative biomarker panels could be used to i) build a candidate model classifying grade 1 vs. grade 3 tumors, ii) demonstrate the molecular heterogeneity among grade 2 tumors, and iii) potentially re-classify several of the grade 2 tumors to more like grade 1 or grade 3 tumors. This could, in the long-term run, lead to improved prognosis, by which the patients could benefit from improved tailored care. PMID:28650989

  4. Breast tumor angiogenesis analysis using 3D power Doppler ultrasound

    NASA Astrophysics Data System (ADS)

    Chang, Ruey-Feng; Huang, Sheng-Fang; Lee, Yu-Hau; Chen, Dar-Ren; Moon, Woo Kyung

    2006-03-01

    Angiogenesis is the process that correlates to tumor growth, invasion, and metastasis. Breast cancer angiogenesis has been the most extensively studied and now serves as a paradigm for understanding the biology of angiogenesis and its effects on tumor outcome and patient prognosis. Most studies on characterization of angiogenesis focus on pixel/voxel counts more than morphological analysis. Nevertheless, in cancer, the blood flow is greatly affected by the morphological changes, such as the number of vessels, branching pattern, length, and diameter. This paper presents a computer-aided diagnostic (CAD) system that can quantify vascular morphology using 3-D power Doppler ultrasound (US) on breast tumors. We propose a scheme to extract the morphological information from angiography and to relate them to tumor diagnosis outcome. At first, a 3-D thinning algorithm helps narrow down the vessels into their skeletons. The measurements of vascular morphology significantly rely on the traversing of the vascular trees produced from skeletons. Our study of 3-D assessment of vascular morphological features regards vessel count, length, bifurcation, and diameter of vessels. Investigations into 221 solid breast tumors including 110 benign and 111 malignant cases, the p values using the Student's t-test for all features are less than 0.05 indicating that the proposed features are deemed statistically significant. Our scheme focuses on the vascular architecture without involving the technique of tumor segmentation. The results show that the proposed method is feasible, and have a good agreement with the diagnosis of the pathologists.

  5. Tumor tissue protein signatures reflect histological grade of breast cancer.

    PubMed

    Skoog, Petter; Ohlsson, Mattias; Fernö, Mårten; Rydén, Lisa; Borrebaeck, Carl A K; Wingren, Christer

    2017-01-01

    Histological grade is one of the most commonly used prognostic factors for patients diagnosed with breast cancer. However, conventional grading has proven technically challenging, and up to 60% of the tumors are classified as histological grade 2, which represents a heterogeneous cohort less informative for clinical decision making. In an attempt to study and extend the molecular puzzle of histologically graded breast cancer, we have in this pilot project searched for additional protein biomarkers in a new space of the proteome. To this end, we have for the first time performed protein expression profiling of breast cancer tumor tissue, using recombinant antibody microarrays, targeting mainly immunoregulatory proteins. Thus, we have explored the immune system as a disease-specific sensor (clinical immunoproteomics). Uniquely, the results showed that several biologically relevant proteins reflecting histological grade could be delineated. In more detail, the tentative biomarker panels could be used to i) build a candidate model classifying grade 1 vs. grade 3 tumors, ii) demonstrate the molecular heterogeneity among grade 2 tumors, and iii) potentially re-classify several of the grade 2 tumors to more like grade 1 or grade 3 tumors. This could, in the long-term run, lead to improved prognosis, by which the patients could benefit from improved tailored care.

  6. Role of myoepithelial cells in breast tumor progression.

    PubMed

    Pandey, Puspa Raj; Saidou, Jamila; Watabe, Kounosuke

    2010-01-01

    Myoepithelial cells form a semi-continuous protective sheet separating the human breast epithelium and the surrounding stroma. They suppress stromal invasion of tumor cells by the secretion of various anti-angiogenic and anti-invasive factors. The disruption of this cell layer results in the release of the growth factors, angiogenic factors, and reactive oxygen species causing an alteration in the microenvironment. This helps in the proliferation of surrounding cells and increases the invasiveness of tumor cells. Two theories are proposed for the mechanism of tumor epithelial cells progression from in situ to invasive stage. According to the first theory, tumor cell invasion is triggered by the overproduction of proteolytic enzymes by myoepithelial cells and surrounding tumor cells. The second theory states that tumor invasion is a multistep process, the interactions between damaged myoepithelial cells and the immunoreactive cells trigger the release of basement membrane degrading enzymes causing tumor progression. Further studies in understanding of molecular mechanism of myoepithelial cell functions in tumor suppression may lead to the identification of novel therapeutic targets for breast cancer.

  7. 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology

    PubMed Central

    Nelson, Erik R.; Wardell, Suzanne E.; Jasper, Jeff S.; Park, Sunghee; Suchindran, Sunil; Howe, Matthew K.; Carver, Nicole J.; Pillai, Ruchita V.; Sullivan, Patrick M.; Sondhi, Varun; Umetani, Michihisa; Geradts, Joseph; McDonnell, Donald P.

    2014-01-01

    Hypercholesterolemia is a risk factor for estrogen receptor (ER) positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here we show that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and Liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1, and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer. PMID:24288332

  8. Expression Quantitative Trait loci (QTL) in tumor adjacent normal breast tissue and breast tumor tissue

    PubMed Central

    Quiroz-Zárate, Alejandro; Harshfield, Benjamin J.; Hu, Rong; Knoblauch, Nick; Beck, Andrew H.; Hankinson, Susan E.; Carey, Vincent; Tamimi, Rulla M.; Hunter, David J.; Quackenbush, John; Hazra, Aditi

    2017-01-01

    We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of genome-wide association studies (GWAS) of breast cancer, the majority of which are located in intergenic or intronic regions. To explore regulatory impacts of these variants we conducted expression quantitative loci (eQTL) analyses on tissue samples from 376 invasive postmenopausal breast cancer cases in the Nurses’ Health Study (NHS) diagnosed from 1990–2004. Expression analysis was conducted on all formalin-fixed paraffin-embedded (FFPE) tissue samples (and on 264 adjacent normal samples) using the Affymetrix Human Transcriptome Array. Significance and ranking of associations between tumor receptor status and expression variation was preserved between NHS FFPE and TCGA fresh-frozen sample sets (Spearman r = 0.85, p<10^-10 for 17 of the 21 Oncotype DX recurrence signature genes). At an FDR threshold of 10%, we identified 27 trans-eQTLs associated with expression variation in 217 distinct genes. SNP-gene associations can be explored using an open-source interactive browser distributed in a Bioconductor package. Using a new a procedure for testing hypotheses relating SNP content to expression patterns in gene sets, defined as molecular function pathways, we find that loci on 6q14 and 6q25 affect various gene sets and molecular pathways (FDR < 10%). Although the ultimate biological interpretation of the GWAS-identified variants remains to be uncovered, this study validates the utility of expression analysis of this FFPE expression set for more detailed integrative analyses. PMID:28152060

  9. Expression Quantitative Trait loci (QTL) in tumor adjacent normal breast tissue and breast tumor tissue.

    PubMed

    Quiroz-Zárate, Alejandro; Harshfield, Benjamin J; Hu, Rong; Knoblauch, Nick; Beck, Andrew H; Hankinson, Susan E; Carey, Vincent; Tamimi, Rulla M; Hunter, David J; Quackenbush, John; Hazra, Aditi

    2017-01-01

    We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of genome-wide association studies (GWAS) of breast cancer, the majority of which are located in intergenic or intronic regions. To explore regulatory impacts of these variants we conducted expression quantitative loci (eQTL) analyses on tissue samples from 376 invasive postmenopausal breast cancer cases in the Nurses' Health Study (NHS) diagnosed from 1990-2004. Expression analysis was conducted on all formalin-fixed paraffin-embedded (FFPE) tissue samples (and on 264 adjacent normal samples) using the Affymetrix Human Transcriptome Array. Significance and ranking of associations between tumor receptor status and expression variation was preserved between NHS FFPE and TCGA fresh-frozen sample sets (Spearman r = 0.85, p<10^-10 for 17 of the 21 Oncotype DX recurrence signature genes). At an FDR threshold of 10%, we identified 27 trans-eQTLs associated with expression variation in 217 distinct genes. SNP-gene associations can be explored using an open-source interactive browser distributed in a Bioconductor package. Using a new a procedure for testing hypotheses relating SNP content to expression patterns in gene sets, defined as molecular function pathways, we find that loci on 6q14 and 6q25 affect various gene sets and molecular pathways (FDR < 10%). Although the ultimate biological interpretation of the GWAS-identified variants remains to be uncovered, this study validates the utility of expression analysis of this FFPE expression set for more detailed integrative analyses.

  10. Percutaneous image-guided ablation of breast tumors: an overview.

    PubMed

    Sag, Alan A; Maybody, Majid; Comstock, Christopher; Solomon, Stephen B

    2014-06-01

    Percutaneous non-surgical image-guided ablation is emerging as an adjunct or alternative to surgery in the management of benign and malignant breast tumors. This review covers the current state of the literature regarding percutaneous image-guided ablation modalities, clinical factors regarding patient selection, and future directions for research.

  11. Percutaneous Image-Guided Ablation of Breast Tumors: An Overview

    PubMed Central

    Sag, Alan A.; Maybody, Majid; Comstock, Christopher; Solomon, Stephen B.

    2014-01-01

    Percutaneous non-surgical image-guided ablation is emerging as an adjunct or alternative to surgery in the management of benign and malignant breast tumors. This review covers the current state of the literature regarding percutaneous image-guided ablation modalities, clinical factors regarding patient selection, and future directions for research. PMID:25049447

  12. High Residual Tumor Rate for Early Breast Cancer Patients Receiving Vacuum-assisted Breast Biopsy

    PubMed Central

    He, Xiao-Fang; Ye, Feng; Wen, Jia-Huai; Li, Shuai-Jie; Huang, Xiao-Jia; Xiao, Xiang-Sheng; Xie, Xiao-Ming

    2017-01-01

    Purpose: The objective of study is aiming to investigate the residual tumor rate after Vacuum-assisted Breast Biopsy (VABB) for early breast cancer excision and the efficacy of mammogram and ultrasound in detecting residual tumor. Methods: Patients who underwent VABB and were confirmed with breast cancer in Sun Yat-sen University Cancer Center from 2010 to 2015 were reviewed retrospectively. The residual tumor rate determined by histological examination was calculated, and then was compared with the results estimated by mammogram and ultrasound which were performed post VABB but before subsequent surgery. Univariate and multivariate analysis (logistic regression) were carried out to identify the independent risk factors associated with residual tumor. Results: In total, 126 eligible patients with early breast cancer were recruited for this study, of whom 79 (62.7%) had residual tumor and 47 (37.3 %) underwent complete excision. The residual tumor rates for lesions < 10mm, lesions 10 to 20 mm and lesions >20mm in size were 55.0%, 68.9% and 53.1%, respectively. The complete excision rates estimated by mammogram and ultrasound were 76.5% and 73.9%, with a negative predictive value of only 46.2% and 50.6%, respectively. In the multivariate logistic regression analysis, no specific factors were found associated with risk of residual tumor (all P > 0.05). Conclusions: There was a high residual tumor rate after VABB in early breast cancer. Both mammogram and ultrasound could not effectively detect the residual tumor after VABB. PMID:28261351

  13. Assessment of breast tumor size in electrical impedance scanning

    NASA Astrophysics Data System (ADS)

    Kim, Sungwhan

    2012-02-01

    Electrical impedance scanning (EIS) is a newly introduced imaging technique for early breast cancer detection. In EIS, we apply a sinusoidal voltage between a hand-held electrode and a scanning probe placed on the breast skin to make current travel through the breast. We measure induced currents (Neumann data) through the scanning probe. In this paper, we investigate the frequency-dependent behavior of the induced complex potential and show how the frequency differential of the current measurement on the scanning probe reflects the contrast in complex conductivity values between surrounding and cancerous tissues. Furthermore, we develop the formula for breast tumor size using the frequency differential of the current measurement and provide its feasibility.

  14. Breast Field Cancerization: Isolation and Comparison of Telomerase-Expressing Cells in Tumor and Tumor Adjacent, Histologically Normal Breast Tissue

    PubMed Central

    Trujillo, Kristina A.; Hines, William C.; Vargas, Keith M.; Jones, Anna C.; Joste, Nancy E.; Bisoffi, Marco; Griffith, Jeffrey K.

    2011-01-01

    Telomerase stabilizes chromosomes by maintaining telomere length, immortalizes mammalian cells, and is expressed in more than 90% of human tumors. However, the expression of human telomerase reverse transcriptase (hTERT) is not restricted to tumor cells. We have previously shown that a subpopulation of human mammary epithelial cells (HMEC) in tumor-adjacent, histologically normal (TAHN) breast tissues expresses hTERT mRNA at levels comparable with levels in breast tumors. In the current study, we first validated a reporter for measuring levels of hTERT promoter activity in early-passage HMECs and then used this reporter to compare hTERT promoter activity in HMECs derived from tumor and paired TAHN tissues 1, 3, and 5 cm from the tumor (TAHN-1, TAHN-3, and TAHN-5, respectively). Cell sorting, quantitative real-time PCR, and microarray analyses showed that the 10% of HMECs with the highest hTERT promoter activity in both tumor and TAHN-1 tissues contain more than 95% of hTERT mRNA and overexpress many genes involved in cell cycle and mitosis. The percentage of HMECs within this subpopulation showing high hTERT promoter activity was significantly reduced or absent in TAHN-3 and TAHN-5 tissues. We conclude that the field of normal tissue proximal to the breast tumors contains a population of HMECs similar in hTERT expression levels and in gene expression to the HMECs within the tumor mass and that this population is significantly reduced in tissues more distal to the tumor. PMID:21775421

  15. 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.

  16. [Considerations in rational use of tumor markers in breast carcinoma].

    PubMed

    Crombach, G

    1998-04-22

    The objective of this review is to determine clinical practical guidelines for the use of serum tumor markers in the care of breast cancer patients outside of clinical trials. Mucin antigens (CA 15-3, MCA, CA 549) and CEA are established markers in breast cancer. Owing to their low sensitivity, none of these markers can be recommended for screening, diagnosis or staging. During follow-up, increasing marker levels may indicate recurrence 3-6 months earlier than clinical and radiological examinations in about 40-50% of patients. However, the clinical benefit of this lead-time is not established. Tumor markers are able to monitor response to treatment in 70-80% of patients with metastatic breast cancer. However, paradoxical changes of the markers especially in the beginning of treatment, the insufficient concordance with tumor activity in 20-30% of the women, and the lack of curative therapy regimens limit the prospective clinical use of the markers in the individual patient. Therefore, marker changes require confirmation by radiological methods in most cases. The present data are insufficient to recommend routine use of tumor markers alone for monitoring breast cancer patients after primary treatment or during palliative therapy. However, in the absence of readily measurable disease (e. g. bone metastases) continuously increasing marker levels may be used to indicate treatment failure. If high-dose chemotherapy in metastatic breast cancer renders to be effective, the clinical impact of tumor markers will increase considerably. Until that time, the analytical performance and the sensitivity of the established marker assays should be improved, and the clinical role of newer marker tests (TPS, CA 27.29) should be evaluated.

  17. Characterization of spontaneous breast tumor in tree shrews (Tupaia belangeri chinenesis).

    PubMed

    Xia, Hou-Jun; Wang, Chun-Yan; Zhang, Hai-Lin; He, Bao-Li; Jiao, Jian-Lin; Chen, Ce-Shi

    2012-02-01

    Breast cancer is a common malignant tumor. It is essential to develop suitable animal models for discovering novel preventive and therapeutic approaches. Tree shrews (Tupaia belangeri chinensis) have a closer evolutionary relationship with humans than do rodents, which have been widely used in laboratory research. Spontaneous breast tumors were identified in tree shrews in 1960s; however, no detailed studies about tree shrew breast tumors have been conducted to date. Here, we characterized a spontaneous breast tumor from tree shrews by Haematoxylin Eosin (H&E) staining. This tumor was identified as a papillary tumor. Immunohistochemical staining (IHC) for progesterone receptor (PR), Ki-67 and cleaved caspase-3 showed that tumor cells were positive for PR, highly proliferative, and less apoptotic compared to normal breast epithelial cells. Thus, the spontaneous tumor of tree shrew is very close to human papillary tumors in terms of morphology and pathology and we concluded that tree shrew may be a suitable animal model for breast cancer research.

  18. 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

  19. Serum tumor markers in patients with breast cancer.

    PubMed

    Lumachi, Franco; Basso, Stefano M M

    2004-10-01

    Several serum tumor markers have been investigated in patients with breast cancer for assessing outcome, predicting recurrence and monitoring the therapeutic response. There is a general consensus concerning their limited application in diagnosing malignancy; however, serum tumor markers can be considered for the early detection of recurrence. The most effective markers for this indication are cancer antigens (CA)15-3 and 27.29, and c-erbB-2, although their efficacy in establishing disease progression has not been determined to date. In terms of evaluating prognosis and predicting response to therapy, only the expression of c-erbB-2 has clinical evidence. To conclude, at present, no serum tumor marker is cost effective, and none can be used with confidence in the decision making regarding breast cancer patients.

  20. Metabolomic profiling of breast tumors using ductal fluid

    PubMed Central

    Do Canto, Luisa Matos; Marian, Catalin; Varghese, Rency S.; Ahn, Jaeil; Da Cunha, Patricia A.; Willey, Shawna; Sidawy, Mary; Rone, Janice D.; Cheema, Amrita K.; Luta, George; Nezami ranjbar, Mohammad R.; Ressom, Habtom W.; Haddad, Bassem R.

    2016-01-01

    Identification of new biomarkers for breast cancer remains critical in order to enhance early detection of the disease and improve its prognosis. Towards this end, we performed an untargeted metabolomic analysis of breast ductal fluid using an ultra-performance liquid chromatography coupled with a quadrupole time-of-light (UPLC-QTOF) mass spectrometer. We investigated the metabolomic profiles of breast tumors using ductal fluid samples collected by ductal lavage (DL). We studied fluid from both the affected breasts and the unaffected contralateral breasts (as controls) from 43 women with confirmed unilateral breast cancer. Using this approach, we identified 1560 ions in the positive mode and 538 ions in the negative mode after preprocessing of the UPLC-QTOF data. Paired t-tests applied on these data matrices identified 209 ions (positive and negative modes combined) with significant change in intensity level between affected and unaffected control breasts (adjusted P-values <0.05). Among these, 83 ions (39.7%) showed a fold change (FC) >1.2 and 66 ions (31.6%) were identified with putative compound names. The metabolites that we identified included endogenous metabolites such as amino acid derivatives (N-Acetyl-DL-tryptophan) or products of lipid metabolism such as N-linoleoyl taurine, trans-2-dodecenoylcarnitine, lysophosphatidylcholine LysoPC(18:2(9Z,12Z)), glycerophospholipids PG(18:0/0:0), and phosphatidylserine PS(20:4(5Z,8Z,11Z,14Z). Generalized LASSO regression further selected 21 metabolites when race, menopausal status, smoking, grade and TNM stage were adjusted for. A predictive conditional logistic regression model, using the LASSO selected 21 ions, provided diagnostic accuracy with the area under the curve of 0.956 (sensitivity/specificity of 0.907/0.884). This is the first study that shows the feasibility of conducting a comprehensive metabolomic profiling of breast tumors using breast ductal fluid to detect changes in the cellular microenvironment of

  1. Therapeutic effects of dendrosomal solanine on a metastatic breast tumor.

    PubMed

    Mohsenikia, Maryam; Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Khori, Vahid; Arjmand Abbassi, Yasaman; Vesovic, Milica; Soleymani, Ali; Najafi, Farhood

    2016-03-01

    Our previous studies showed that alpha-solanine can inhibit tumor growth in cell culture and animal models of breast cancer. However, solanine is insoluble in common solvents; therefore, we developed a special nanoparticle with high-capacity solubility. The present study is aimed to deliberate the therapeutic effects of dendrosomal solanine (DNS) on a metastatic breast tumor in vitro and in vivo. After DNS preparation and dosing procedures, forty-five mice were equally divided into five groups to investigate the anti-metastatic effects of DNS on mammary tumor-bearing mice. Compared to solanine, DNS significantly suppressed the proliferation of 4 T1 cells in a dose- and time-dependent manner. DNS showed a remarkable safety rate of up to 10mg/kg. A significant decrease in white blood-cell count was seen at 20mg/kg DNS in comparison with control animals. Mice treated with DNS had smaller tumor volume (mm(3)) in comparison with control and solanine groups. Moreover, the incidence of the breast tumor metastases was about 67% in the control animals, where as solanine and DNS 1mg/kg were about 22% and 0%, respectively. Furthermore, the number of metastases per mouse varied from one to three. The tissues of tumor, brain, liver, spleen, and lung showed higher expression levels of Bcl-2 but lower expression levels of Bax, MMP-2, MMP-9, mTOR, and Akt in DNS-treated mice than control and solanine groups. The findings suggest that DNS has a more impactful therapeutic effect than solanine on 4 T1-induced breast tumorigenesis via influencing the tissue microenvironment. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. 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

  3. Angiogenic Signaling in Living Breast Tumor Models

    DTIC Science & Technology

    2010-06-01

    harmonic generation imaging of the diseased state osteogenesis imperfecta : experiment and simulation,” Biophys. J. 94(11), 4504–4514 (2008). 3. O...biopsies, mouse models of breast cancer, and dermis from mouse models of Osteogenesis Imperfecta (OIM) [1–5,7]. The F/B ratio revealed the length scale of...interest in discriminating skin with Osteogenesis Imperfecta [2] from normal dermis [2] and SHG F/B ratio measurements have been used to help determine

  4. Comprehensive lipid profiling of plasma in patients with benign breast tumor and breast cancer reveals novel biomarkers.

    PubMed

    Yang, Li; Cui, Xinge; Zhang, Ningning; Li, Min; Bai, Yu; Han, Xiaohong; Shi, Yuankai; Liu, Huwei

    2015-07-01

    Abnormal lipid metabolism is a common feature in most solid tumors, and occurs in early stages of the tumor progression. As benign breast tumor is different from malignant tumor of breast cancer, it is particularly important to take benign breast tumor into consideration when investigating cancer biomarkers. In this study, by using a normal-phase/reversed-phase two-dimensional liquid chromatography-mass spectrometry (NP/RP 2D LC-MS) method, we conducted comprehensive lipid profiling in human plasma obtained from six benign breast tumor patients and five breast cancer patients, as well as nine healthy controls. As a result, 512 lipid species were successfully identified. Principal component analysis allowed clear separation of the three groups. Quantitative analysis revealed that many lipid contents were similar in benign and malignant breast tumors compared with controls, and these were proposed as potential breast tumor biomarkers other than breast cancer biomarkers. Two phosphatidylinositol (PI) species, including PI (16:0/16:1) and PI (18:0/20:4), could differentiate between benign and malignant breast tumors, as well as breast cancer patients and healthy controls, indicating that they could be utilized as potential breast cancer biomarkers. In addition, PI (16:0/18:1), phosphatidylglycerol (36:3), and glucosylceramide (d18:1/15:1) were demonstrated to be potential biomarkers to evaluate the level of malignancy of breast tumor. Taken together, our results indicate the usefulness of lipid profiling in the discrimination between patients with breast cancer and non-carcinoma lesions, which might provide assistance in clinical diagnosis.

  5. [Color Doppler in breast tumor pathology].

    PubMed

    Balu-Maestro, C; Bruneton, J N; Giudicelli, T; Chauvel, C; Hery, M D

    1991-11-01

    Colour Doppler findings in a series of 63 cases of breast tumours and 19 cases of lymph node enlargements are reported. Colour Doppler signals of abnormal flow are found in 68.5 percent of the cancers, in 42.8 percent of metastatic lymph nodes and in 10 percent of benign lesions. There was bidirectional flow in 80 percent of all the cases. In cases of malignant tumours, the signal was correlated with the size and location of the lesions most often found peripherally. Presently, this technique appears to be of little value in determining whether a primary malignant tumour of the breast is malignant or benign. It does appear to be useful, first to follow-up cancers during initial chemotherapy (partial regression of the signal and of tumour volume) and secondly, in the diagnosis of metastatic lymph nodes with a specificity of 100 percent in our series. Colour Doppler is on the contrary difficult to interprete after conservative treatment of breast cancer because of post-radiotherapy tissue remodelling.

  6. 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.

  7. 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.

  8. TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.

    PubMed

    Győrffy, Balázs; Bottai, Giulia; Lehmann-Che, Jacqueline; Kéri, György; Orfi, László; Iwamoto, Takayuki; Desmedt, Christine; Bianchini, Giampaolo; Turner, Nicholas C; de Thè, Hugues; André, Fabrice; Sotiriou, Christos; Hortobagyi, Gabriel N; Di Leo, Angelo; Pusztai, Lajos; Santarpia, Libero

    2014-05-01

    Breast cancers (BC) carry a complex set of gene mutations that can influence their gene expression and clinical behavior. We aimed to identify genes driven by the TP53 mutation status and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negative BC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC analyses of each gene expression according to TP53 mutation status were performed. The prognostic value of genes with the highest AUC were assessed in a large dataset of untreated, and neoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was the most significant gene correlated with TP53 status, and the most significant prognostic marker in all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated in different BC cell lines. We also assessed the effects of a potent small molecule inhibitor of MPS1, SP600125, alone and in combination with chemotherapy. Consistent with the gene expression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reduction in cell viability and a significant increase in cell death, selectively in TP53-mutated BC cells. Furthermore, the chemical inhibition of MPS1 sensitized BC cells to conventional chemotherapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated kinase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, and that SP600125 warrant further development in future clinical trials.

  9. Phyllodes Tumor of the Breast: Analysis of 48 Patients

    PubMed Central

    Kılıç, Murat Özgür; Terzioğlu, Serdar Gökay; Bozkurt, Betül; Dağlar, Gül

    2016-01-01

    Objective Phyllodes tumor (PT) is a rare biphasic breast neoplasm that accounts for less than 1% of all breast tumors. The aim of this study was to evaluate the clinicopathologic features, diagnostic difficulties, and therapeutic outcomes of patients with PT. Materials and Methods A total of 48 female patients who underwent surgery for PT were included in the study. Patient characteristics, clinicopathologic features of tumors, diagnostic findings, surgical outcomes, adjuvant therapies, and follow-up findings were retrospectively evaluated. Results The mean age of patients was 35 years. Painless breast mass was the most common (85.4%) presenting symptom. Total excision with at least 1 cm macroscopic clear margins was the most frequently performed (87.5%) surgery. Most patients (n=34, 70.8%) had benign PT; however, borderline and malignant tumors were found in 9 (18.8%) and 5 (10.4%) patients, respectively. During the mean follow-up period of approximately 30 months, local and distant recurrence was detected in three (6.3%) patients and one (2.1%) patient, respectively. Patients with malignant PT had larger tumors than those with benign and borderline PTs (p=0.010). No significant difference in other clinical, diagnostic, and pathologic characteristics was found between the groups. Conclusion PT can be easily confused with other breast masses such as fibroadenoma due to the non-specific clinical and radiologic findings. Surgical excision with at least 1 cm clear margins is of great importance to reduce the risk of local recurrence. However, recurrence can develop even after appropriate surgery, thus patients should be closely followed up after surgery. PMID:28331755

  10. High tumor budding stratifies breast cancer with metastatic properties.

    PubMed

    Salhia, Bodour; Trippel, Mafalda; Pfaltz, Katrin; Cihoric, Nikola; Grogg, André; Lädrach, Claudia; Zlobec, Inti; Tapia, Coya

    2015-04-01

    Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (p ≤ 0.03) and lymphatic invasion (p ≤ 0.015). In CB high tumor budding was significantly (p = 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.

  11. ADAMTS6 suppresses tumor progression via the ERK signaling pathway and serves as a prognostic marker in human breast cancer

    PubMed Central

    Xie, Keqi; Wang, Zhu; Wang, Yanping; Zheng, Hong

    2016-01-01

    A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is involved in tumor development. However, how ADAMTS6 influences cancer remains unknown. We investigated the biological function and clinical implications of ADAMTs6 in breast cancer (BC). Its functional significance in BC cell lines was confirmed by ADAMTs6 overexpression or downregulation both in vitro and in vivo studies. Enhanced ADAMTS6 expression suppressed cell migration, invasion, and tumorigenesis, whereas knockdown promoted these characteristics. The extracellular signal-regulated kinase (ERK) pathway was partially involved in ADAMTS6-mediated inhibition of BC development, and miR-221-3p was identified as a predicted target for ADAMTS6. Results from the luciferase assay confirmed that miR-221-3p directly inhibited ADAMTS6 expression by binding its 3′-untranslated region. In addition, immunohistochemistry data from specimens from 182 BC patients showed that high ADAMTS6 expression was significantly correlated with favorable disease-free survival (DFS, p = 0.045). Subgroup analysis of patients with ER positive, PR positive or HER-2 negative tumors revealed that high ADAMTS6 expression more strongly extended DFS compared to low expression (p = 0.004, p = 0.009, p = 0.017). Multivariate analyses confirmed that ADAMTS6 expression was an independent risk factor for DFS (p = 0.011). Together, these data demonstrate that ADAMTS6 inhibits tumor development by regulating the ERK pathway via binding of miR-221-3p. Thus, its expression may be a potential prognostic biomarker for BC. PMID:27542224

  12. Low molecular weight (LMW) cyclin E can bypass letrozole-induced G1 arrest in human breast cancer cells and tumors

    PubMed Central

    Akli, Said; Bui, Tuyen; Wingate, Hannah; Biernacka, Anna; Moulder, Stacy; Tucker, Susan L.; Hunt, Kelly K.; Keyomarsi, Khandan

    2009-01-01

    Purpose Low-molecular-weight cyclin E (LMW-E) in breast cancer cells induces genomic instability, and resistance to inhibition by p21, p27, and fulvestrant therapy. Here, we sought to determine if LMW-E renders breast cancer cells unresponsive to aromatase inhibitors (AI), elucidate the mechanism of such resistance and ascertain if inhibitors of LMW-E associated kinase activity could overcome this resistance. Experimental Design Antiproliferative effects of the AIs, were examined in aromatase-overexpressing MCF-7/Ac1 cells in the presence or absence of full length and LMW-E. Inhibition of LMW cyclin E kinase activity by roscovitine (a CDK inhibitor) was examined in letrozole-unresponsive MCF-7/Ac1 cells. The role of LMW-E and CDK2 in mediating recurrence following AI treatment were also assessed in breast cancer patients. Results Overexpression of LMW-E in postmenopausal patients was associated with a poor prognosis. Letrozole, but not exemestane or anastrozole, mediated a pronounced G1 arrest in MCF-7/Ac1 cells. Androstenedione (AD)-induced G1 exit correlated with increased cyclin E-associated kinase activity and increased CDK2 levels. Letrozole treatment inhibited cyclin E-CDK2 kinase activity by preventing the AD-induced increase in CDK2. LMW-E bypassed this effect and rendered the cells resistant to letrozole inhibition. Roscovitine blocked the AD-induced increase in CDK2 and LMW-E overexpression could not bypass this effect. Lastly, breast cancer patients whose tumor overexpress LMW-E were not responsive to AI treatment. Conclusions Roscovitine treatment can reverse intrinsic or acquired resistance to letrozole due to LMW-E expression in breast cancer cells. These data support clinical investigation of CDK2 inhibitor therapy for postmenopausal women with ER-positive, LMW-E-expressing breast cancer. PMID:20145171

  13. Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

    DTIC Science & Technology

    2015-11-01

    Months 1-60). Uses pathology samples of 4 breast tumor types to determine if SHG can predict metastatic outcome. ~4x50=200 samples. Produces an...in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology . Other studies indicate that collagen’s organizational...collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer. Methods: Tumors were implanted into murine

  14. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2005-05-01

    AD_ Award Number: DAMD17-03-1-0353 TITLE: Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers...30 Apr 2005 4. TITLE AND SUBTITLE Sa. CONTRACT NUMBER Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable...year of the project, we have investigated the cyclophosphamide dose effects on rat breast tumor hemodynamics and also monitored how tumor hemodynamics

  15. Family history of cancer associated with breast tumor clinicopathological features.

    PubMed

    Ricks, Luisel J; Ewing, Altovise; Thompson, Nicole; Harrison, Barbara; Wilson, Bradford; Richardson, Finie; Carter-Nolan, Pamela; Spencer, Cherie; Laiyemo, Adeyinka; Williams, Carla

    2014-07-01

    Hereditary breast cancers have unique clinicopathological characteristics. Therefore, the objective of this study was to establish the relationship between self-reported family history of cancer and clinicopathological features in breast cancer patients from Washington, DC. Data on incident breast cancer cases from 2000 to 2010 were obtained from the Washington, DC Cancer Registry. Variables such as estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptor status, as well as stage and grade, were analyzed in those that self-reported with (n = 1,734) and without a family history of cancer (n = 1,712). The breast cancer molecular subtypes were compared when ER, PR, and HER2 statuses were available. Furthermore, tumor characteristics were compared by race/ethnicity. Regression and chi-square analyses were performed. A report of family history was associated with age (OR = 1.27 95 % CI: 1.09-1.48; p < 0.0001), high grade tumors (OR = 1.29 95 % CI: 1.05-1.58; p = 0.02), and having ER and PR negative breast cancer (OR = 1.26 95 % CI: 1.02-1.57; p = 0.029). When tumor characteristics were compared by race/ethnicity, those that self-reported as African American with a family history had a higher frequency of ER negative tumors (OR = 1.51 95 % CI: 1.09-2.08; p = 0.008), PR negative tumors (OR = 1.46 95 % CI: 1.09-1.94; p = 0.028), grade 3 tumors (OR = 1.42 95 % CI: 1.05-1.93; p < 0.0001), and ER/PR negative tumors (OR = 1.5 95 % CI: 1.088-2.064; p = 0.01). These results suggest that a positive family history of cancer in African Americans should increase suspicions of hereditary cancer. Therefore, behavioral risk reduction activities, such as collecting a family history, may reduce late stage diagnosis and cancer mortality.

  16. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2006-05-01

    ABSTRACT For the third year of the project, we have investigated the radiotherapy effects on rat breast tumor hemodynamics and also analyzed our... radiotherapy , photodynamic therapy, and conventional chemotherapy. 5. Acknowledgements: This work was supported in part by the Department of Defense Breast ...AD_________________ Award Number: DAMD17-03-1-0353 TITLE: Monitoring of Breast Tumor Response to

  17. 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.

  18. [Pulmonary Metastasis from a Phyllodes Tumor of the Breast Developing Sixteen Years after Initial Surgery].

    PubMed

    Chang, Sung-Soo; Nakano, Takayuki; Okamoto, Taku; Takabatake, Daisuke

    2015-11-01

    We report a case of solitary pulmonary metastasis from a phyllodes tumor of the breast appearing 16 years after initial surgery. The patient was a 56-year-old woman who had undergone surgical extirpation of a left breast tumor diagnosed as phyllodes tumor (borderline malignancy) in 1998, and a right breast tumor diagnosed as fibromatosis in 2000. Sixteen years after the initial operation, she consulted our hospital because of a chest X-ray abnormality detected at a screening examination. Chest computed tomography revealed a well defined nodular shadow in the left upper lobe of the lung. Surgery was done since primary lung cancer was suspected. However, pathological diagnosis was a pulmonary metastasis from the phyllodes tumor of the left breast. Right breast tumor was also diagnosed as a metastasis from the left breast tumor by histopathological re-evaluation.

  19. Angiogenic Signaling in Living Breast Tumor Models

    DTIC Science & Technology

    2007-06-01

    to ordering) than backscattered SHG intensity. Figure 5 shows an F/B image of a thin section of a TG1-1 mouse mammary tumor grown in the mammary fat...we plan on testing our full sample set anyway, as well as explore unfixed tissue sections. Polarization measurements of mouse collagen. Our...indicator of subtle matrix damage during MPFRAP or SFAFRAP. Our first measurements were control measurements, where we measured rho in mouse tail collagen

  20. Angiogenic Signaling in Living Breast Tumor Models

    DTIC Science & Technology

    2008-06-01

    A.S. Kamoun-Goldrat and M.F. Le Merrer, "Animal models of osteogenesis imperfecta and related syndromes," J. Bone Miner. Metab. 25, 211-8 (2007...in the tumor reactive stroma. Therefore these optical properties may be useful in studying genetic disorders of collagen, such as in Osteogenesis ... Imperfecta [26]. Acknowledgments This work is supported by Department of Defense grant W81XWH-05-1-0396. We thank Drs. Ania Majewska and Dr. Julie

  1. Ultrasound imaging of breast tumor perfusion and neovascular morphology.

    PubMed

    Hoyt, Kenneth; Umphrey, Heidi; Lockhart, Mark; Robbin, Michelle; Forero-Torres, Andres

    2015-09-01

    A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic

  2. Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment.

    PubMed

    Ménétrier-Caux, Christine; Faget, Julien; Biota, Cathy; Gobert, Michael; Blay, Jean-Yves; Caux, Christophe

    2012-08-01

    Regulatory T cells (Treg) have been reported of poor prognosis for overall survival in primary breast tumors (BT). As CCL22 plays a major role in Treg recruitment within primary BT we deciphered the mechanisms involved in the CCL22 production by breast epithelial tumor cells and propose herein the major role of their innate immune recognition in this production.

  3. Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment

    PubMed Central

    Ménétrier-Caux, Christine; Faget, Julien; Biota, Cathy; Gobert, Michael; Blay, Jean-Yves; Caux, Christophe

    2012-01-01

    Regulatory T cells (Treg) have been reported of poor prognosis for overall survival in primary breast tumors (BT). As CCL22 plays a major role in Treg recruitment within primary BT we deciphered the mechanisms involved in the CCL22 production by breast epithelial tumor cells and propose herein the major role of their innate immune recognition in this production. PMID:22934274

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

    DOE PAGES

    Xu, Zhe; Wu, Chaochao; Xie, Fang; ...

    2014-10-28

    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 andmore » 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. Additionally, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. In conclusion, peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.« less

  5. 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.

  6. Malignant phyllodes tumor of the breast: treatment and prognosis.

    PubMed

    Mituś, Jerzy; Reinfuss, Marian; Mituś, Jerzy W; Jakubowicz, Jerzy; Blecharz, Pawel; Wysocki, Wojciech M; Skotnicki, Piotr

    2014-01-01

    Surgery remains the mainstay of the treatment in patients with malignant phyllodes tumor of the breast (MPTB); however, the extent of surgery (breast conserving surgery [BCS] versus mastectomy) and the role of adjuvant radiotherapy have been controversial. We report a single institution's experience with MPTB. We discuss controversial therapeutic aspects of this rare tumor. Seventy patients with MPTB treated primarily with surgery were evaluated. The mean age was 50 years (21-76), and the mean size of the tumor was 6 cm. Thirty-four (48.6%) patients were treated with total mastectomy, and 36 (51.4%) were treated with BCS (lumpectomy or wide local excision). Microscopic surgical margins were free of tumor in all cases. In 64 (91.4%) patients, margins were ≥1 cm. Remaining 6 (8.6%) patients treated with BCS margins were <1 cm and subsequently radiotherapy was performed. Among 70 patients, 58 (82.9%) had no evidence of disease (NED) after 5 years. The extent of surgery was not significantly related to the 5-year NED survival rates (82.4% in patients who underwent mastectomy and 83.3% in patients who underwent BCS only or BCS with adjuvant irradiation). The 5-year NED survival rates in BCS (tumor-free margin ≥1 cm) and BCS with irradiation (tumor-free margin <1 cm) groups were identical (83.3%). Our data support the potential use of BCS in patients with MPTB. Mastectomy is indicated only if tumor-free margins cannot be obtained by BCS. Adjuvant radiotherapy may be considered if tumor-free margins are <1 cm.

  7. Periareolar incision for the management of benign breast tumors.

    PubMed

    Kong, Xiangnan; Chen, Xi; Jiang, Liyu; Ma, Tingting; Han, Baosan; Yang, Qifeng

    2016-11-01

    Benign breast tumors (BBTs) are common in women. The traditional surgical resection method for the various types of BBT leaves obvious scars and affects the appearance of the breast. The present study introduces the experience of a single institution in the treatment of BBT by periareolar incision. The clinical data of 153 patients (182 breasts) with BBT who had undergone a resection via a periareolar incision between January 2010 and December 2012 in Qilu Hospital, Shandong University (Jinan, Shandong, China), was retrospectively analyzed. All incisions were primary healing. Of the 153 patients, 1 (0.7%) developed a hematoma and 2 (1.3%) developed slight nipple ischemia. No infections or other complications were observed. During 1 month to 3 years of follow-up, the cosmetic effects were assessed. Periareolar incision is not only suitable for all types of breast surgery for benign tumor resection, but also has the advantage of a hidden incision, a small scar, no ischemic necrosis of the nipple areola, high patient satisfaction and good post-operative cosmetic effect. The technique is therefore a good surgical incision choice that is worthy of note.

  8. [Breast cancer in Morocco: phenotypic profile of tumors].

    PubMed

    Khalil, Ahmadaye Ibrahim; Bendahhou, Karima; Mestaghanmi, Houriya; Saile, Rachid; Benider, Abdellatif

    2016-01-01

    Breast cancer is most common in women and it is among the leading causes of cancer related deaths. The curability of this type of tumor is increasing thanks to screening programs and treatment advances which have certainly enhanced patient survival. But challenges remain, particularly in respect of phenotypic instability of cancer cells. The aim of this study was to analyse the phenotypic profile of breast cancer in patients treated at Mohammed VI Cancer Treatment Center over the years 2013-2014. We conducted a cross-sectional study over a two-year period, including the cases of breast cancer treated in our Center. Data were collected from patients medical records and analyzed using Epi Info software. 1277 patients were treated in our Center. 99.5% were females, mean age 50.20 ± 11.34 years. The most common histological type was invasive ductal carcinoma (80.7% of cases). It was diagnosed at an early stage (56,9%). The most common molecular phenotype was luminal A (41.4% of cases). Luminal B, HER2 and triple negatives occurred in 10.4%, 6.3%, 11.2% of cases respectively. The study of tumor phenotype in patients with breast cancer helps clinician make treatment choice and policy makers implement programs against this disease.

  9. Periareolar incision for the management of benign breast tumors

    PubMed Central

    Kong, Xiangnan; Chen, Xi; Jiang, Liyu; Ma, Tingting; Han, Baosan; Yang, Qifeng

    2016-01-01

    Benign breast tumors (BBTs) are common in women. The traditional surgical resection method for the various types of BBT leaves obvious scars and affects the appearance of the breast. The present study introduces the experience of a single institution in the treatment of BBT by periareolar incision. The clinical data of 153 patients (182 breasts) with BBT who had undergone a resection via a periareolar incision between January 2010 and December 2012 in Qilu Hospital, Shandong University (Jinan, Shandong, China), was retrospectively analyzed. All incisions were primary healing. Of the 153 patients, 1 (0.7%) developed a hematoma and 2 (1.3%) developed slight nipple ischemia. No infections or other complications were observed. During 1 month to 3 years of follow-up, the cosmetic effects were assessed. Periareolar incision is not only suitable for all types of breast surgery for benign tumor resection, but also has the advantage of a hidden incision, a small scar, no ischemic necrosis of the nipple areola, high patient satisfaction and good post-operative cosmetic effect. The technique is therefore a good surgical incision choice that is worthy of note. PMID:27899991

  10. Tumor Suppressor Genes in Early Breast Cancer and its Progression

    DTIC Science & Technology

    1997-09-01

    Yamakawa K., Akiyama F., Kasumi F., Sakamoto G. and Nakamura Y. Allelotype of breast cancer: cumulative allele losses promote tumor progression in...and Cancer 4:113-121,1992. 18. Sato T., Akiyama F., Sakamoto G., Kasumi F. and Nakamura Y. Accumulation of genetic alterations and progression of...identified Proc. Natl. Acad. USA 87; 7737-7741, 1990. 23. Saito H., Inazawa J., Saito S., Kasumi F., Koi S., Sagae S., Kudo R., Saito J., Noda K. and

  11. 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.

  12. Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation

    PubMed Central

    Ouderkirk-Pecone, Jessica L.; Goreczny, Gregory J.; Chase, Sharon E.; Tatum, Arthur H.; Turner, Christopher E.; Krendel, Mira

    2016-01-01

    Despite advancing therapies, thousands of women die every year of breast cancer. Myosins, actin-dependent molecular motors, are likely to contribute to tumor formation and metastasis via their effects on cell adhesion and migration and may provide promising new targets for cancer therapies. Using the MMTV-PyMT murine model of breast cancer, we identified Myosin 1e (MYO1E) as a novel tumor promoter. Tumor latency in mice lacking MYO1E was significantly increased, and tumors formed in the absence of MYO1E displayed unusual papillary morphology, with well-differentiated layers of epithelial cells covering fibrovascular cores, rather than solid sheets of tumor cells typically observed in this cancer model. These tumors were reminiscent of papillary breast cancer in humans that is typically non-invasive and often cured by tumor excision. MYO1E-null tumors exhibited decreased expression of the markers of cell proliferation, which was recapitulated in primary tumor cells derived from MYO1E-null mice. In agreement with our findings, meta-analysis of patient survival data indicated that MYO1E expression level was associated with reduced recurrence-free survival in basal-like breast cancer. Overall, our data suggests that MYO1E contributes to breast tumor malignancy and regulates the differentiation and proliferation state of breast tumor cells. PMID:27329840

  13. Evolutionary pathways in BRCA1-associated breast tumors.

    PubMed

    Martins, Filipe C; De, Subhajyoti; Almendro, Vanessa; Gönen, Mithat; Park, So Yeon; Blum, Joanne L; Herlihy, William; Ethington, Gabrielle; Schnitt, Stuart J; Tung, Nadine; Garber, Judy E; Fetten, Katharina; Michor, Franziska; Polyak, Kornelia

    2012-06-01

    BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.

  14. 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

  15. [Mamography and core biopsy value in diagnosis of nonpalpable breast tumors].

    PubMed

    Ostapenko, Valerijus; Mikalauskas, Tadas; Bruzas, Saulius; Mudenas, Algimantas; Sabonis, Jonas; Tutkus, Jonas; Meskauskas, Raimundas; Miliauskas, Povilas; Jackevicius, Algirdas; Grinyte, Laima

    2004-01-01

    Nonpalpable breast tumors are of great importance in order to achieve early diagnosis and improve the treatment results of breast cancer. Three hundred and sixty six patients with such pathology were investigated at the Institute of Oncology, Vilnius University. The core biopsy was performed for all patients. Benign breast tumors were diagnosed to 260 patients and conservative treatment was administered to patients with benign breast disease. One hundred and six patients with diagnosed or suspected nonpalpable breast carcinoma underwent surgery. In 64 patients (63.7%) invasive or non-invasive breast carcinoma (0 and 1(st) stage - 71.9%) was diagnosed. The diagnostic algorithm of nonpalpable breast tumor was described. The techniques of surgery for nonpalpable breast tumors and the results of treatment are discussed.

  16. Detection of posteriorly located breast tumors using gold nanoparticles: a breast-mimicking phantom study.

    PubMed

    Ren, Liqiang; Wu, Di; Fajardo, Laurie L; Li, Yuhua; Zheng, Bin; Liu, Hong

    2014-01-01

    Accurately depicting breast tumors located posteriorly, close to the chest wall musculature, with conventional mammography is a technical challenge. This study demonstrates the proof of concept of an x-ray fluorescence mapping (XFM) technique to address this issue. A tissue-equivalent gel phantom is designed to mimic structures in the central part of a compressed breast. The posterior aspect of the breast and adjacent pectoralis major muscle are represented by another 10-mm-thickness breast tissue simulation phantom (BR12) that is attached to the back of the gel phantom as a region of interest (ROI). Two gold nanoparticle (GNP) solutions are embedded into the ROI to simulate varying GNP uptake within breast lesions. The ROI is imaged through performing the XFM technique with an x-ray pencil-beam and a single spectrometer. A 2D mapping of the middle plane in the ROI demonstrates feasibility and matches well the known spatial distribution and different GNP concentrations. 3D reconstruction of the ROI is easily rendered by repeating the 2D mapping process. XFM system geometry and its insensitivity to attenuation coefficients of breast tissue components are unique characteristics that may complement conventional mammography and improve the detection of breast cancers located posteriorly, adjacent to or overlying the chest wall musculature.

  17. Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment.

    PubMed

    Ouyang, Liquan; Chang, Weilong; Fang, Bin; Qin, Jieting; Qu, Xincai; Cheng, Fanjun

    2016-12-20

    Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects.

  18. Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment

    PubMed Central

    Ouyang, Liquan; Chang, Weilong; Fang, Bin; Qin, Jieting; Qu, Xincai; Cheng, Fanjun

    2016-01-01

    Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects. PMID:27996037

  19. Molecular pathogenesis of progression and recurrence in breast phyllodes tumors

    PubMed Central

    Jara-Lazaro, Ana Richelia; Tan, Puay Hoon

    2009-01-01

    Breast phyllodes tumors are rare fibroepithelial neoplasms that need to be distinguished from the common morphologically similar fibroadenomas, because phyllodes tumors can recur and progress to malignancy. Their potentially recurring and metastasizing behavior is attributed to their stromal characteristics, for which categorization between benign, borderline and malignant tumors have not been universally established. Previous clonality studies revealing monoclonal stromal cells versus a polyclonal epithelial component theorized that phyllodes tumors are mainly stromal neoplasms, possibly arising from fibroadenomas. More recent chromosomal imbalances in both epithelium and stroma have challenged this theory to favor neoplasia of both epithelium and stroma, with initial interdependence between the two components. Inverse correlations between epithelial and stromal overexpression for various biological markers like estrogen receptor, p53, c-kit, Ki-67, endothelin-1, epidermal growth factor receptor, heparan sulfate, in addition to findings of epithelial Wnt signalling with stromal insulin growth factors and beta-catenin expression, suggest an initial epithelial-stromal interdependence at the benign phase. Upon progression to malignancy, the stroma is hypothesized to assume an autonomous growth overriding any epithelial influence. Frequent genetic alterations are chromosomal gains of 1q and losses at chromosome 13. Acquisition of new genetic imbalances within the tumor consistent with intratumoral heterogeneity, and subclones within histologically benign phyllodes tumors that recur or metastasize are the current theories explaining these tumors' unpredictable clinical behavior. PMID:19966935

  20. [Phyllodes tumor of the breast: analysis of 8 patients].

    PubMed

    Sabban, F; Collinet, P; Lucot, J-P; Boman, F; Leroy, J-L; Vinatier, D

    2005-05-01

    Phyllodes tumors of breast are rare and usually benign. These are histologically fibro-epithelial tumors similar to fibroadenomas. Histological confirmation on the operative specimen is required to establish the diagnosis and histological pronostic of phyllode tumors. We reviewed 8 cases of phyllodes tumors and the literature to report the circumstances of occurrence of these tumors, and their specific clinical diagnosis, therapeutic, prognostic features. 62.5% of patients were nulliparous. The mean age at diagnosis was 33.4 years. Mean tumor size was 3.75 cm. Tumours predominated on the right side (87.5%) and upper-outer quadrant (62.5%). Imaging findings were helpful for diagnosis. Aspiration cytology demonstrated the phyllode tumor in 43% of patients. Wide tumorectomy was performed in seven patients. One patient underwent mastectomy and radiotherapy and chemotherapy. The recurrence rate (37.5%) justifies wide margin excision. There were no deaths in our series. and conclusion. These results together with those reported in the literature show that the loco-regional and general spread depends on margin surgery.

  1. Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation.

    PubMed

    Johnson, Kevin C; Koestler, Devin C; Cheng, Chao; Christensen, Brock C

    2014-02-01

    Age is a key risk factor for breast cancer and epigenetic alterations may contribute to age-related increases in breast cancer risk, though the relation of age-related methylation in normal breast tissues with altered methylation in breast tumors is unclear. We investigated the relation of age with DNA methylation in normal breast tissues genome-wide using two data sets from the Gene Expression Omnibus (GEO) database (GSE32393 and GSE31979). We validated our observations in an independent set of normal breast tissues, examined age-related methylation in normal breast for enrichment of genomic features, and compared age-related methylation in normal tissue with methylation alterations in breast tumors. Between the two array-based methylation data sets, there were 204 CpG loci with significant (P<0.05) and consistent age-related methylation, 97% of which were increases in methylation. Our validation sets confirmed the direction of age-related DNA methylation changes in all measured regions. Among the 204 age-related CpG loci, we observed a significant enrichment for CpG islands (P = 8.7E-6) and polycomb group protein target genes (P = 0.03). In addition, 24 of the 204 CpGs with age-related methylation in normal breast were significantly differentially methylated between normal and breast tumor tissues. We identified consistent age-related methylation changes in normal breast tissue that are further altered in breast tumors and may represent early events contributing to breast carcinogenesis. This work identifies age-related methylation in normal breast tissue and begins to deconstruct the contribution of aging to epigenetic alterations present in breast tumors.

  2. Desmoid Tumor of the Chest Wall Mimicking Recurrent Breast Cancer: Multimodality Imaging Findings

    PubMed Central

    Choi, Kyeong A; An, Yeong Yi

    2016-01-01

    Desmoid tumor of breast is a rare benign, locally aggressive tumor with a high recurrence rate. It has been associated with scar from previous breast surgery or trauma. Especially in breast cancer patients with previous operation history, it may simulate recurrent breast cancer clinically and radiologically. We presented multimodality imaging findings (ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography/computed tomography) of chest wall desmoid tumor mimicking recurrent breast cancer in a 38-year-old patient with a history of left modified mastectomy. The desmoid tumor is a rare benign tumor that should be considered in the differential diagnosis of malignant local tumor recurrence after breast cancer operation. Biopsy was required for accurate diagnosis and wide local excision was its appropriate surgical management. PMID:27895871

  3. 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.

  4. Identification of Substances for Ubiquitin-Dependent Proteolysis During Breast Tumor Progression

    DTIC Science & Technology

    2008-10-01

    post-replication repair of UV- damaged DNA ATXN3 Machado - Joseph disease gene product, nucleotide excision repair MARK2 Microtubule binding protein...changes in ubiquitylation activity accompany the progression of breast tumors to more advanced disease . These activities likely drive breast tumor...We have found that key changes in ubiquitylation activity occur as breast tumors progress to advanced disease . The substrates of this activity

  5. Simultaneous Monitoring of Vascular Oxygenation and Tissue Oxygen Tension of Breast Tumors Under Hyperbaric Oxygen Exposure

    DTIC Science & Technology

    2008-04-01

    chemotherapy and radiotherapy (37). In summary, changes in breast tumor temperature and vascular oxygenation have been simultaneously measured using a multi...Oxygenation and Tissue Oxygen Tension of Breast Tumors Under Hyperbaric Oxygen Exposure PRINCIPAL INVESTIGATOR: Mengna Xia...W81XWH-04-1-0411 Breast Tumors under Hyperbaric Oxygen Exposure 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT

  6. Comparative Proteomics of Tumor and Paired Normal Breast Tissue Highlights Potential Biomarkers in Breast Cancer.

    PubMed

    Da Costa, Gustavo Góes; Gomig, Talita Helen Bombardelli; Kaviski, Rodrigo; Santos Sousa, Karla; Kukolj, Caroline; De Lima, Rubens Silveira; De Andrade Urban, Cicero; Cavalli, Iglenir J; Ribeiro, Enilze M S F

    2015-01-01

    Breast cancer is the most common type of cancer among women worldwide, and about 57,000 new cases are expected for the Brazilian population in 2015. Elucidation of protein expression and modification is essential for the biological understanding, early diagnosis and therapeutics of breast cancer. The main objectives of the study are comparison between the proteome of tumor and paired non-tumor breast cancer tissues, describing all identified proteins, highlighting the ones most differentially expressed and comparing the data with existing literature. The five paired samples from patients with invasive ductal carcinoma were analyzed by 2-DE and MS. We collected 161 identified spots corresponding to 110 distinct proteins. Forty-three differentially-expressed spots were common to at least two samples, and the ten proteins with the highest-fold changes were CASPE, ENOG, TPM1, CAPG, VIME, TPM3, TRFE, PDIA6, WDR61 and PDIA3. Metabolic enzymes and proteins with binding functions were the most representative functional classes of proteins with increased and decreased expression in tumor tissue respectively. Taking the fold change as a parameter, we point to future targets to be studied by functional methods in a search for biomarkers for initiation and progress of breast cancer. Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

  7. GATA3 expression in clinically useful groups of breast carcinoma: a comparison with GCDFP15 and mammaglobin for identifying paired primary and metastatic tumors.

    PubMed

    Yang, Yuqiong; Lu, Shanming; Zeng, Wenqin; Xie, Shoucheng; Xiao, Shengjun

    2017-02-01

    .593 <0.75) (both P<.05). In conclusion, GATA3 expression did not show the same sensitivity for the clinically useful groups of breast cancer. GATA3 expression is positively correlated with ER-positive, PR-positive, and HER2-positive carcinomas. In addition, the matched primary and metastatic tumor expression of GATA3 shows good coincidence. We propose the careful selection of GATA3 for identifying hormone receptor negativity of breast cancer, especially in the case of triple-negative breast cancer.

  8. The expression of succinate dehydrogenase in breast phyllodes tumor.

    PubMed

    Choi, Junjeong; Kim, Do Hee; Jung, WooHee; Koo, Ja Seung

    2014-10-01

    The purpose of this study is to investigate the expression of succinate dehydrogenase (SDH)A, SDHB, and HIF-1α in phyllodes tumors and the association with clinic-pathologic factors. Using tissue microarray (TMA) for 206 phyllodes tumor cases, we performed immunohistochemical stains for SDHA, SDHB, and HIF-1α and analyzed their expression in regard to clinicopathologic parameters of each case. The cases were comprised of 156 benign, 34 borderline, and 16 malignant phyllodes tumors. The expression of stromal SDHA and epithelial- and stromal- SDHB increased as the tumor progressed from benign to malignant (P⟨0.001). There were five stromal SDHA-negative cases and 31 stromal SDHB-negative cases. SDHB negativity was associated with a lower histologic grade (P=0.054) and lower stromal atypia (P=0.048). Univariate analysis revealed that a shorter disease free survival (DFS) was associated with stromal SDHB high-positivity (P=0.013) and a shorter overall survival (OS) was associated with high-positivity of stromal SDHA and SDHB (P⟨0.001 and P⟨0.001, respectively). The multivariate Cox analysis with the variables stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, stromal SDHA expression, and stromal SDHB expression revealed that stromal overgrowth was associated with a shorter DFS (hazard ratio: 24.78, 95% CI: 3.126-196.5, P=0.002) and a shorter OS (hazard ratio: 176.7, 95% CI: 8.466-3691, P=0.001). In conclusion, Tumor grade is positively correlated with SDHA and SDHB expression in the tumor stroma in phyllodes tumors of the breast. This result may be attributed to the increased metabolic demand in high grade tumors.

  9. 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; 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

    2013-01-01

    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

  10. 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.

  11. Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

    PubMed

    Mazumdar, Abhijit; Poage, Graham M; Shepherd, Jonathan; Tsimelzon, Anna; Hartman, Zachary C; Den Hollander, Petra; Hill, Jamal; Zhang, Yun; Chang, Jenny; Hilsenbeck, Susan G; Fuqua, Suzanne; Kent Osborne, C; Mills, Gordon B; Brown, Powel H

    2016-08-01

    Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.

  12. [The actions of diffusion weighted imaging (DWI) and dynamic contrast enhanced MRI in differentiating breast tumors].

    PubMed

    Luo, Yi; Yu, Jianqun; Chen, Dongdong; Xu, Zhongzi; Zeng, Hanjiang

    2013-12-01

    We studied the actions of diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) in differentiating breast tumors. From January 2010 to February 2012, we retrospectively analyzed data of 95 cases with breast tumor pathologically confirmed from DWI and DCE-MRI. We compared the ADC value, time-intensity curve (TIC) and DCE-MRI parameters between breast tumors, and calculated the sensitivity and specificity for differentiating breast tumors. The results were as follows: (1) On DWI, mean ADC value of malignant tumor was lower than that of benign tumor (P < 0.05). For differentiating breast malignant tumors from benign neoplasm, a cut-off ADC value of 1.2 x 10(-3) mm2/s achieved a sensitivity of 74.1% and specificity of 70.3%. (2) On DCE-MRI, early enhancement ratio (EER) value of malignant tumor was higher than that of benign tumor whereas value of time to peak (Tpeak) and maximal enhancement ratio (SImax) were lower than that of benign tumor (all P < 0.05). As for TIC, type II and III were more frequently seen in malignant tumor than in benign tumor whereas type I was more common in benign tumor than in malignant tumor (all P < 0.05). For differentiating breast malignant tumors from benign neoplasm, DCE-MRI obtained a sensitivity of 89.7% and specificity of 70.3%. (3) For differentiating breast malignant tumors from benign neoplasm, ADC value together with TIC obtained a sensitivity of 79.3% and specificity of 78.4%. Malignant or benign breast tumors could have their own unique characteristics on DWI and DCE-MRI. These characteristics might be helpful for differentiating these tumors.

  13. Breast tumor detection using continuous wave light source

    NASA Astrophysics Data System (ADS)

    Zhao, Shiyin; O'Leary, Maureen A.; Nioka, Shoko; Chance, Britton

    1995-05-01

    The detection of small amounts of indocyanine green (ICG) in small volumes would suggest its potential use in the detection of early breast tumors. While phased array has already shown its ability to sharply localize small amounts of ICG in the picomole region, the question has arisen, what would be the comparable sensitivity of continous light systems for the same purpose? If this were a comparable sensitivity, the advantages of the simplest of opto- electronic systems and the use of light intensity not limited to those available under FDA regulations for laser diodes could be realized. In this research work, we investigate two methods of enhancing the contrast agent between diseased and healthy tissue using low frequency amplitude modulated light sources. The first method exploits the symmetry between the left and right breast and the second exploits the cylindrical symmetry of the breast. Both effect are enhanced by the use of an injected contrast agent (ICG). Based on the theory and model study, several human subjects cases were studied in the Hospital of the University of Pennsylvania. The results show that the peak signal can get about 60 seconds after ICG injection through the vein and then will take few minutes to get back to the baseline. The half decay time and maximum (Delta) OD are dependent of the characteristics of the breast tissue.

  14. Breast tumor characterization using near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Kang, Kyung A.; Chance, Britton; Zhao, Shiyin; Srinivasan, Sudhakar; Patterson, E.; Troupin, R.

    1993-09-01

    NIR time resolved spectroscopy (TRS) is one of the most feasible methods which can be used for the characterization of biological systems, due to its non-invasive nature and safety features in measurement. Breast cancer is the leading cause of death in women ages 40 - 44 and accounts for 32% of all cancer diagnosis in women. The occurrence rate is as high as one out of nine women in the USA. Breast cancer is the most common form of cancer and the second leading cause of cancer death in North America. Therefore, it is natural for researchers in the field of NIR spectroscopy to have strong interest in optical properties of normal and abnormal breast tissue. One of the main interests of NIR spectroscopy in breast cancer is the localization of the tumor. Another important feature is to characterize an anomaly non- invasively since more than 75% of mammographical anomalies are found to be benign. This could reduce the anxiety that the patients would have, as well as lower the clinical expense for the biopsy and operation (approximately $4,000 per a case).

  15. 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.

  16. Analysis of CUL-5 expression in breast epithelial cells, breast cancer cell lines, normal tissues and tumor tissues

    PubMed Central

    Fay, Michael J; Longo, Kenneth A; Karathanasis, George A; Shope, David M; Mandernach, Craig J; Leong, Jason R; Hicks, Alfred; Pherson, Kenneth; Husain, Amyna

    2003-01-01

    Background The chromosomal location of CUL-5 (11q 22-23) is associated with LOH in breast cancer, suggesting that CUL-5 may be a tumor suppressor. The purpose of this research was to determine if there is differential expression of CUL-5 in breast epithelial cells versus breast cancer cell lines, and normal human tissues versus human tumors. The expression of CUL-5 in breast epithelial cells (HMEC, MCF-10A), and breast cancer cells (MCF-7, MDA-MB-231) was examined using RT-PCR, Northern blot analysis, and Western blot analysis. The expression of mRNA for other CUL family members (CUL-1, -2, -3, -4A, and -4B) in these cells was evaluated by RT-PCR. A normal human tissue expression array and a cancer profiling array were used to examine CUL-5 expression in normal human tissues and matched normal tissues versus tumor tissues, respectively. Results CUL-5 is expressed at the mRNA and protein levels by breast epithelial cells (HMEC, MCF-10A) and breast cancer cells (MCF-7, MDA-MB-231). These cells also express mRNA for other CUL family members. The normal human tissue expression array revealed that CUL-5 is widely expressed. The cancer profiling array revealed that 82% (41/50) of the breast cancers demonstrated a decrease in CUL-5 expression versus the matched normal tissue. For the 50 cases of matched breast tissue there was a statistically significant ~2.2 fold decreased expression of CUL-5 in tumor tissue versus normal tissue (P < 0.0001). Conclusions The data demonstrate no apparent decrease in CUL-5 expression in the breast cancer cell lines (MCF-7, MDA-MB-231) versus the breast epithelial cells (HMEC, MCF-10A). The decrease in CUL-5 expression in breast tumor tissue versus matched normal tissue supports the hypothesis that decreased expression of CUL-5 may play a role in breast tumorigenesis. PMID:14641918

  17. Significance of Micrometastases: Circulating Tumor Cells and Disseminated Tumor Cells in Early Breast Cancer

    PubMed Central

    Oakman, Catherine; Pestrin, Marta; Bessi, Silvia; Galardi, Francesca; Di Leo, Angelo

    2010-01-01

    Adjuvant systemic therapy targets minimal residual disease. Our current clinical approach in the adjuvant setting is to presume, rather than confirm, the presence of minimal residual disease. Based on assessment of the primary tumor, we estimate an individual’s recurrence risk. Subsequent treatment decisions are based on characteristics of the primary tumor, with the presumption of consistent biology and treatment sensitivity between micrometastases and the primary lesion. An alternative approach is to identify micrometastatic disease. Detection of disseminated tumor cells (DTC) in the bone marrow and circulating tumor cells (CTC) from peripheral blood collection may offer quantification and biocharacterization of residual disease. This paper will review the prognostic and predictive potential of micrometastatic disease in early breast cancer. PMID:24281114

  18. Chemokine C-C motif ligand 18 expression correlates with tumor malignancy in breast cancer.

    PubMed

    Gao, J; Li, Z-H; Tang, W; Wu, Q-N; Liu, G-H; Zheng, W-B

    2015-09-01

    To investigate whether CCL18 is involved in breast cancer, and the relationship between CCL18 and MVD (MVD was recognized by CD34) which is a well-accepted angiogenic maker of multiple cancers including breast cancer. Immunohistochemistry staining for CCL18 and CD34 was performed on 179 cases, including 29 normal cases as control, 47 cases with benign breast diseases, and 103 cases with breast cancer. We found that CCL18 was significantly up-regulated in breast cancer samples as compared with benign tumors or normal breast tissues. Moreover, the expression level of CCL18 increased with the size of tumors, the number of lymph node metastasis, and advancing tumor stage, suggesting that CCL18 expression correlates with tumor malignancy scales. At the same time, we found that MVD was also significantly over-expressed in cancer tissues as compared with normal control group and benign tumor group, but it was not significantly differentially expressed among tumors with different malignancy scale like CCL18, while the expression of MVD in CCL18 positive breast cancer cases was higher than in the CCL18 negative breast cancer cases (P=0.016, P<0.05). CCL18 is involved in the development of breast cancer. CCL18 is a better biomarker than MVD in determining whether the tumor is malignant and the severity of malignancy of breast cancer. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  19. Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy.

    PubMed

    Parissenti, Amadeo M; Guo, Baoqing; Pritzker, Laura B; Pritzker, Kenneth P H; Wang, Xiaohui; Zhu, Mu; Shepherd, Lois E; Trudeau, Maureen E

    2015-08-01

    In a prior substudy of the CAN-NCIC-MA.22 clinical trial (ClinicalTrials.gov identifier NCT00066443), we observed that neoadjuvant chemotherapy reduced tumor RNA integrity in breast cancer patients, a phenomenon we term "RNA disruption." The purpose of the current study was to assess in the full patient cohort the relationship between mid-treatment tumor RNA disruption and both pCR post-treatment and, subsequently, disease-free survival (DFS) up to 108 months post-treatment. To meet these objectives, we developed the RNA disruption assay (RDA) to quantify RNA disruption and stratify it into 3 response zones of clinical importance. Zone 1 is a level of RNA disruption inadequate for pathologic complete response (pCR); Zone 2 is an intermediate level, while Zone 3 has high RNA disruption. The same RNA disruption cut points developed for pCR response were then utilized for DFS. Tumor RDA identified >fourfold more chemotherapy non-responders than did clinical response by calipers. pCR responders were clustered in RDA Zone 3, irrespective of tumor subtype. DFS was about 2-fold greater for patients with tumors in Zone 3 compared to Zone 1 patients. Kaplan-Meier survival curves corroborated these findings that high tumor RNA disruption was associated with increased DFS. DFS values for patients in zone 3 that did not achieve a pCR were similar to that of pCR recipients across tumor subtypes, including patients with hormone receptor positive tumors that seldom achieve a pCR. RDA appears superior to pCR as a chemotherapy response biomarker, supporting the prospect of its use in response-guided chemotherapy.

  20. Immunohistochemical and molecular markers in breast phyllodes tumors.

    PubMed

    Korcheva, Veselina B; Levine, Judith; Beadling, Carol; Warrick, Andrea; Countryman, Gayle; Olson, Neal R; Heinrich, Michael C; Corless, Christopher L; Troxell, Megan L

    2011-03-01

    Phyllodes tumors of the breast are diagnostically and managerially enigmatic, as their malignant potential is difficult to predict based on the standard morphologic criteria. Thus, there is a need for additional markers of biologic potential. Although a number of ancillary tests have been reported, consensus in the literature is lacking. We studied 38 cellular fibroadenomas and phyllodes tumors of various grade (World Health Organization benign, borderline, and malignant) with a panel of immunohistochemical stains (p53, CD117, phospho-Histone3, mdm2, cdk4) and screened 26 of the tumors for mutations across 30 cancer-related genes using PCR and mass-spectrometry based methods. p53 and phospho-Histone3 (mitotic marker) showed increased staining in higher grade phyllodes tumors. CD117, mdm2, and cdk4 showed no difference in expression across different grades of phyllodes tumors. Mutational analysis revealed an S8R substitution in FBX4 (an E3 ubiquitin ligase) in 3 cases: 1 benign and 2 borderline. The S8R substitution seems to be more common in phyllodes tumors (11.5%) as compared with other cancers. FBX4 S8R cases had high cyclin D1 expression, but this finding was not specific. Our data support earlier studies showing that p53 has potential use in pathologic assessment of phyllodes tumors, and we newly characterized phospho-Histone3 for this application. Further studies are needed to characterize the molecular pathogenesis of the phyllodes tumors, as we were unable to identify activating mutations despite screening for a large panel of activating hotspot mutations. The significance of the FBX4 substitution deserves further investigation.

  1. Role of tumor markers and circulating tumors cells in the management of breast cancer.

    PubMed

    Saad, Ayman; Abraham, Jame

    2008-06-01

    Along with various imaging modalities, serologic tumor markers such as CA 15-3 and CA 27.29 have been used for decades to monitor treatment response in patients with metastatic breast cancer (MBC). Despite the frequent use of these markers, they lack high sensitivity and specificity for breast cancer progression. The prognostic significance of these markers remains indeterminate because of the conflicting outcome of many clinical trials. The circulating tumor cell (CTC) test has recently been studied in clinical trials in patients with MBC. Some of the studies showed that high levels of CTCs are correlated with poor survival in MBC. An intergroup trial is underway to determine the implication of changing treatment based on the CTC level. This article will discuss the current data on these markers, with special emphasis on the CTC test. The potential clinical utility of these markers will also be discussed.

  2. Terahertz Imaging of Three-Dimensional Dehydrated Breast Cancer Tumors

    NASA Astrophysics Data System (ADS)

    Bowman, Tyler; Wu, Yuhao; Gauch, John; Campbell, Lucas K.; El-Shenawee, Magda

    2017-03-01

    This work presents the application of terahertz imaging to three-dimensional formalin-fixed, paraffin-embedded human breast cancer tumors. The results demonstrate the capability of terahertz for in-depth scanning to produce cross section images without the need to slice the tumor. Samples of tumors excised from women diagnosed with infiltrating ductal carcinoma and lobular carcinoma are investigated using a pulsed terahertz time domain imaging system. A time of flight estimation is used to obtain vertical and horizontal cross section images of tumor tissues embedded in paraffin block. Strong agreement is shown comparing the terahertz images obtained by electronically scanning the tumor in-depth in comparison with histopathology images. The detection of cancer tissue inside the block is found to be accurate to depths over 1 mm. Image processing techniques are applied to provide improved contrast and automation of the obtained terahertz images. In particular, unsharp masking and edge detection methods are found to be most effective for three-dimensional block imaging.

  3. Terahertz Imaging of Three-Dimensional Dehydrated Breast Cancer Tumors

    NASA Astrophysics Data System (ADS)

    Bowman, Tyler; Wu, Yuhao; Gauch, John; Campbell, Lucas K.; El-Shenawee, Magda

    2017-06-01

    This work presents the application of terahertz imaging to three-dimensional formalin-fixed, paraffin-embedded human breast cancer tumors. The results demonstrate the capability of terahertz for in-depth scanning to produce cross section images without the need to slice the tumor. Samples of tumors excised from women diagnosed with infiltrating ductal carcinoma and lobular carcinoma are investigated using a pulsed terahertz time domain imaging system. A time of flight estimation is used to obtain vertical and horizontal cross section images of tumor tissues embedded in paraffin block. Strong agreement is shown comparing the terahertz images obtained by electronically scanning the tumor in-depth in comparison with histopathology images. The detection of cancer tissue inside the block is found to be accurate to depths over 1 mm. Image processing techniques are applied to provide improved contrast and automation of the obtained terahertz images. In particular, unsharp masking and edge detection methods are found to be most effective for three-dimensional block imaging.

  4. [Seasonal patterns of breast tumor growth in Far North residents].

    PubMed

    Borisenkov, M F; Bazhenov, S M

    2005-01-01

    Earlier, we established a relationship between sex hormone receptor concentration in tumor and 5-year survival, on the one hand, and seasonality, on the other. The parameters showed a distinct 6-month cycle. That pointed to certain environmental factors which could synchronize hormone-dependent tumor process in the breast of women living in the North. The present study is concerned with a relationship of 6-month rhythm of tumor growth and latitude of residence. Said rhythm was reliably identified as a parameter of 5-year survival in the Far North (68 deg. northern latitude, p < 0.001). Maximum values of 5-year survival were registered in those diagnosed with cancer in winter or summer, while those diagnosed in spring or fall had unfavorable prognosis. Northern magnetic storms recur at 6-month intervals and most frequently in spring and fall. Electromagnetic radiation is known to suppress melatonin production and, that might have stimulated tumor process. Therefore, it is most likely that solar electromagnetic radiation might synchronize hormone-dependent tumor process in women resident in the North.

  5. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    PubMed Central

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  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. Epidemiologic Investigation of a Cluster of Cystosarcoma Phyllodes Tumors of the Female Breast.

    DTIC Science & Technology

    1997-09-01

    AD GRANT NUMBER DAMD17-94-J-4423 TITLE: Epidemiologie Investigation of a Cluster of Cystosarcoma Phyllodes Tumors of the Female Breast PRINCIPAL...SUBTITLE Epidemiologie Investigation of a Cluster of Cystosarcoraa Phyllodes Tumors of the Female Breast 3. REPORT TYPE AND DATES COVERED fAnnual...fibroepithelial tumor composed of an epithelial and a cellular stromal component. A significant number of cases of cystosarcoma phyllodes tumors were

  8. Pleomorphic liposarcoma arising in a malignant phyllodes tumor of breast: A rare occurrence.

    PubMed

    Sancheti, Sankalp M; Sawaimoon, Satyakam K; Ahmed, Rosina

    2015-01-01

    Primary malignant phyllodes tumor of the breast accounts for 0.3-1% of all the tumors of breast and only a couple of cases of pleomorphic liposarcoma (PL) arising in a malignant phyllodes (MP) tumor have been reported. A thorough sampling is most essential in phyllodes tumor, not only to detect high grade component of the neoplasm but also to diagnose heterologous elements in the same lesion elsewhere, as it may affect the prognosis adversely and may have a greater metastatic potential.

  9. 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.

  10. Prognostic factors in male breast cancer: a population-based study.

    PubMed

    Leone, José Pablo; Zwenger, Ariel Osvaldo; Iturbe, Julián; Leone, Julieta; Leone, Bernardo Amadeo; Vallejo, Carlos Teodoro; Bhargava, Rohit

    2016-04-01

    Prognostic factors in male breast cancer (MaBC) are controversial. The objective of this study was to analyze patient characteristics and prognostic factors in MaBC over the last decade. Using the Surveillance, Epidemiology, and End Results program, we extracted MaBC patients diagnosed between 2003 and 2012. Patient characteristics were compared between tumor grades. We conducted univariate and multivariate analyses to determine the effects of each prognostic variable on overall survival (OS). The study included 2992 patients. The majority had ductal (85 %), ER-positive (95.1 %), and PR-positive (86 %) breast cancer; however, only 12.4 % had grade I tumors. Stage I and II disease represented 73 % of cases. There was a significant association between grade III/IV tumors with ductal histology, ER and PR negativity, advanced stage, receipt of mastectomy and radiotherapy, and breast cancer death (all P < 0.05). ER-positive patients had better OS (hazard ratio 0.69, P = 0.03); however, after 7.5 years, OS rates by ER status were similar. In multivariate analysis, older age, grade III/IV tumors, stage IV disease, no surgery, no radiotherapy, ER-negative tumors, and unmarried patients had significantly shorter OS (all P < 0.05). Over the past decade, MaBC has been diagnosed most frequently with early stages of disease and high rates of ER positivity; however, grade I is uncommon. ER positivity is associated with better prognosis, mainly during the first 5 years after diagnosis. Age at diagnosis, tumor grade, stage, surgery, radiotherapy, ER, and marital status have clear impact on OS in MaBC.

  11. Genetic and phenotypic diversity in breast tumor metastases.

    PubMed

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-03-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease. ©2014 AACR

  12. Diffuse reflectance spectral imaging for breast tumor margin assessment

    NASA Astrophysics Data System (ADS)

    Lo, Justin Y.; Dhar, Sulochana; Yu, Bing; Brooke, Martin A.; Kuech, Thomas F.; Jokerst, Nan M.; Ramanujam, Nimmi

    2012-03-01

    Diffuse reflectance spectroscopy has been previously explored as a promising method for providing real-time visual maps of tissue composition to help surgeons determine breast lumpectomy margins and to ensure the complete removal of a tumor during surgery. We present the simple design, validation, and implementation of a compact and cost-effective spectral imaging system for the application of tumor margin assessment. Our new system consists of a broadband source with bandpass filters for illumination and a fabricated custom 16-pixel photodiode imaging array for the detection of diffuse reflectance. The system prototype was characterized in tissue-mimicking phantoms and has an SNR of greater than 40 dB in phantoms, animals, and human tissue. We show proof-of-concept for performing fast, wide-field spectral imaging with a simple, inexpensive design. The strategy also allows for the scaling to higher pixel number and density in future iterations of the system.

  13. Paralemmin-1 is over-expressed in estrogen-receptor positive breast cancers

    PubMed Central

    2012-01-01

    Background Paralemmin-1 is a phosphoprotein lipid-anchored to the cytoplasmic face of membranes where it functions in membrane dynamics, maintenance of cell shape, and process formation. Expression of paralemmin-1 and its major splice variant (Δ exon 8) as well as the extent of posttranslational modifications are tissue- and development-specific. Paralemmin-1 expression in normal breast and breast cancer tissue has not been described previously. Results Paralemmin-1 mRNA and protein expression was evaluated in ten breast cell lines, 26 primary tumors, and 10 reduction mammoplasty (RM) tissues using real time RT-PCR. Paralemmin-1 splice variants were assessed in tumor and RM tissues using a series of primers and RT-PCR. Paralemmin-1 protein expression was examined in cell lines using Western Blots and in 31 ductal carcinomas in situ, 65 infiltrating ductal carcinomas, and 40 RM tissues using immunohistochemistry. Paralemmin-1 mRNA levels were higher in breast cancers than in RM tissue and estrogen receptor (ER)-positive tumors had higher transcript levels than ER-negative tumors. The Δ exon 8 splice variant was detected more frequently in tumor than in RM tissues. Protein expression was consistent with mRNA results showing higher paralemmin-1 expression in ER-positive tumors. Conclusions The differential expression of paralemmin-1 in a subset of breast cancers suggests the existence of variation in membrane dynamics that may be exploited to improve diagnosis or provide a therapeutic target. PMID:22574838

  14. Background Parenchymal Enhancement and Fibroglandular Tissue Proportion on Breast MRI: Correlation with Hormone Receptor Expression and Molecular Subtypes of Breast Cancer

    PubMed Central

    Öztürk, Mesut; Polat, Ahmet Veysel; Süllü, Yurdanur; Tomak, Leman; Polat, Ayfer Kamalı

    2017-01-01

    Objective To assess the relationship between background parenchymal enhancement (BPE) and fibroglandular tissue (FGT) proportion on breast magnetic resonance imaging (MRI) and hormone receptor expression and molecular subtypes in invasive breast cancer. Materials and Methods This retrospective study enrolled 75 breast cancer patients who underwent breast MRI before treatment. T1-weighted images were reviewed to determine the FGT proportion, and contrast-enhanced fat-suppressed T1-weighted images were reviewed to determine BPE. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2-neu (HER2) status, and molecular subtypes of the tumors were compared with the BPE and FGT proportions. Results Women with high BPE tended to have increased rate of ER and PR positive tumors (p=0.018 and p=0.013). FGT proportion was associated with ER positivity (p=0.009), but no significant differences between FGT proportion and PR positivity were found (p=0.256). There was no significant difference between HER2 status and any of the imaging features (p=0.453 and p=0.922). For premenopausal women, both FGT proportion and BPE were associated with molecular subtypes (p=0.025 and p=0.042). FGT proportion was also associated with BPE (p<0.001). Conclusion In women with invasive breast cancer, both high FGT containing breasts and high BPE breasts tended to have ER positive tumors. PMID:28331765

  15. A combining method for tumors detection from near-infrared breast imaging.

    PubMed

    Wang, Zhicheng; Liu, Jian; Tian, Jinwen; Xie, Zeping

    2005-01-01

    This paper introduces the new qualitative and quantitative methods, which can diagnose breast tumors. Qualitative methods include blood vessel display inside and outside of pathological changes part of breast, display of equivalent pixel curves at the part of pathological changes and display of breast tumor image edge. Accordingly, three feature extraction operators are proposed, i.e. the combination operators of anisotropic gradient and smoothing operator, an improved Sobel operator and an edge sharpening operator. Furthermore, quantitative diagnose approaches are discussed based on blood and oxygen contents according to abundant clinical data and pathological mechanism of breast tumors. The results of clinic show that the methods of combining qualitative and quantitative diagnose are effective for breast tumor images, especially for early and potential breast cancer.

  16. 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.

  17. 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.

  18. 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.

  19. The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

    DTIC Science & Technology

    2008-04-01

    Interactions in Breast Cancer PRINCIPAL INVESTIGATOR: Jessica L. Fry CONTRACTING ORGANIZATION: Beth Israel Deaconess Medical Center...The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer 5b. GRANT NUMBER W81XWH-06-1-0460 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...second year of research on the action of ADAM9 isoforms in tumor-stromal interactions focused on the role of endogenous ADAM9 in breast cancer cell

  20. Circulating Tumor Cells in Breast Cancer Patients: An Evolving Role in Patient Prognosis and Disease Progression

    PubMed Central

    Graves, Holly; Czerniecki, Brian J.

    2011-01-01

    In this paper, we examine the role of circulating tumor cells (CTCs) in breast cancer. CTCs are tumor cells present in the peripheral blood. They are found in many different carcinomas but are not present in patients with benign disease. Recent advances in theories regarding metastasis support the role of early release of tumor cells in the neoplastic process. Furthermore, it has been found that phenotypic variation exists between the primary tumor and CTCs. Of particular interest is the incongruency found between primary tumor and CTC HER2 status in both metastatic and early breast cancer. Overall, CTCs have been shown to be a poor prognostic marker in metastatic breast cancer. CTCs in early breast cancer are not as well studied, however, several studies suggest that the presence of CTCs in early breast cancer may also suggest a poorer prognosis. Studies are currently underway looking at the use of CTC level monitoring in order to guide changes in therapy. PMID:21253472

  1. Label-Free Raman Imaging to Monitor Breast Tumor Signatures.

    PubMed

    Manciu, Felicia S; Ciubuc, John D; Parra, Karla; Manciu, Marian; Bennet, Kevin E; Valenzuela, Paloma; Sundin, Emma M; Durrer, William G; Reza, Luis; Francia, Giulio

    2017-08-01

    Although not yet ready for clinical application, methods based on Raman spectroscopy have shown significant potential in identifying, characterizing, and discriminating between noncancerous and cancerous specimens. Real-time and accurate medical diagnosis achievable through this vibrational optical method largely benefits from improvements in current technological and software capabilities. Not only is the acquisition of spectral information now possible in milliseconds and analysis of hundreds of thousands of data points achieved in minutes, but Raman spectroscopy also allows simultaneous detection and monitoring of several biological components. Besides demonstrating a significant Raman signature distinction between nontumorigenic (MCF-10A) and tumorigenic (MCF-7) breast epithelial cells, our study demonstrates that Raman can be used as a label-free method to evaluate epidermal growth factor activity in tumor cells. Comparative Raman profiles and images of specimens in the presence or absence of epidermal growth factor show important differences in regions attributed to lipid, protein, and nucleic acid vibrations. The occurrence, which is dependent on the presence of epidermal growth factor, of new Raman features associated with the appearance of phosphothreonine and phosphoserine residues reflects a signal transduction from the membrane to the nucleus, with concomitant modification of DNA/RNA structural characteristics. Parallel Western blotting analysis reveals an epidermal growth factor induction of phosphorylated Akt protein, corroborating the Raman results. The analysis presented in this work is an important step toward Raman-based evaluation of biological activity of epidermal growth factor receptors on the surfaces of breast cancer cells. With the ultimate future goal of clinically implementing Raman-guided techniques for the diagnosis of breast tumors (e.g., with regard to specific receptor activity), the current results just lay the foundation for

  2. A fuzzy gene expression-based computational approach improves breast cancer prognostication

    PubMed Central

    2010-01-01

    Early gene expression studies classified breast tumors into at least three clinically relevant subtypes. Although most current gene signatures are prognostic for estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancers, few are informative for ER negative/HER2 negative and HER2 positive subtypes. Here we present Gene Expression Prognostic Index Using Subtypes (GENIUS), a fuzzy approach for prognostication that takes into account the molecular heterogeneity of breast cancer. In systematic evaluations, GENIUS significantly outperformed current gene signatures and clinical indices in the global population of patients. PMID:20156340

  3. PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth.

    PubMed

    Gupta, Parul; Wright, Stephen E; Srivastava, Sanjay K

    2015-02-01

    Breast tumors are heterogeneous with a complex etiology. The immune system plays a crucial role in the development of tumors and can facilitate tumor growth pleiotropically. Myeloid derived suppressor cells (MDSCs) generate reactive oxygen species (ROS) and cytokines to suppress T cells, dendritic cells and natural killer (NK) cells. Hence, the inhibition of MDSCs could be an important strategy for anticancer therapeutics. Phenethyl isothiocyanate (PEITC), a bioactive compound present in cruciferous vegetables, is known to have anticancer properties. However, the effects of PEITC administration on the immune system have not been previously reported. In the current study, we evaluated the effects of administering PEITC to immunocompromised NOD-SCID IL2Rγ(-/-) (SCID/NSG) host mice bearing MDA-MB-231 xenografts on MDSCs in the peripheral blood. Our results reveal that oral administration of 12 μmol PEITC attenuated tumor growth by 76%. This was marked tumor-inhibitory phenotype was associated with a significant reduction in the levels of MDSCs bearing the surface markers CD33, CD34 and CD11b in PEITC treated mice, indicating that overall tumor growth suppression by PEITC correlates with inhibition of MDSCs. To the best of our knowledge, this is the first study showing effects of PEITC on MDSCs.

  4. Antitumor activity of an enzyme prodrug therapy targeted to the breast tumor vasculature.

    PubMed

    Van Rite, Brent D; Krais, John J; Cherry, Mohamad; Sikavitsas, Vassilios I; Kurkjian, Carla; Harrison, Roger G

    2013-10-01

    The L-methioninase-annexin V/selenomethionine enzyme prodrug system, designed to target the tumor vasculature and release the methylselenol anticancer drug in the tumor, was tested in mice with implanted MBA-MB-231 breast tumors. This therapy was able to cause a reduction in the size of the tumors during the treatment period. It was shown that L-methioninase-annexin V was uniformly bound at the blood vessel surface in the tumor and also that there was a substantial cutoff of blood flowing through the treated tumor, consistent with the therapy's design. This new approach for enzyme prodrug therapy of breast cancer appears promising.

  5. Tumor-infiltrating lymphocytes in breast cancer according to tumor subtype: Current state of the art.

    PubMed

    Solinas, Cinzia; Carbognin, Luisa; De Silva, Pushpamali; Criscitiello, Carmen; Lambertini, Matteo

    2017-10-01

    The recent success of the immune checkpoint blockade in cancer immunotherapy has modified the treatment algorithms in a variety of aggressive neoplastic diseases. Nevertheless, optimal selection of ideal candidates to these drugs remains a challenge. The presence, location and composition of a pre-existing tumor immune infiltrate seem to impact on the benefit from these treatments. The association between the presence of baseline tumor-infiltrating lymphocytes (TIL) and patients' outcomes has been widely investigated in breast cancer, although immunotherapeutic strategies have historically been less successful with respect to other neoplastic diseases such as melanoma and kidney cancer. TIL extent varies and has different associations with outcomes in the various breast cancer subtypes. Furthermore, the presence of baseline high TIL has been associated with an increased benefit from some chemotherapeutic and targeted agents even though some conflicting results have been observed on this regard. This review aims to summarize the state of the art of TIL in breast cancer with a focus on their assessment, prevalence and clinical implications in the different subtypes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. 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.

  7. 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

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

    PubMed

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

    2015-01-01

    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.

  9. Cerebellar metastases of recurrent phyllodes tumor breast; a rare phenomenon reflecting the unpredictable outcome.

    PubMed

    Singh, Jyotsna; Majumdar, Kaushik; Gupta, Rahul; Batra, Vineeta Vijay

    2015-01-01

    Carcinomas of lung, breast, colon, kidney, and malignant melanomas are the most common malignancies that metastasize to the central nervous system (CNS). Phyllodes tumor is a rare fibroepithelial tumor of the breast, often having unpredictable recurrences, with increasing histological grade and distant metastasis. Malignant forms exist, which may develop distant metastases usually to the lung, pleura, bone, and liver. CNS metastasis of phyllodes tumor is rare and associated with a poor prognosis, with resistance to chemotherapy and radiation. We present a rare case of cerebellar metastasis in recurrent phyllodes tumor breast with subsequent rapid downhill course.

  10. Prevalence of Papillomaviruses, Polyomaviruses, and Herpesviruses in Triple-Negative and Inflammatory Breast Tumors from Algeria Compared with Other Types of Breast Cancer Tumors

    PubMed Central

    Corbex, Marilys; Bouzbid, Sabiha; Traverse-Glehen, Alexandra; Aouras, Hayette; McKay-Chopin, Sandrine; Carreira, Christine; Lankar, Abdelaziz; Tommasino, Massimo; Gheit, Tarik

    2014-01-01

    Background The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC) and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups. Materials and Methods One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria) to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses) using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology. Results Viral DNA was found in 22 (17.9%) of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type) than non-IBC tumors (30% vs. 13%, p<0.04). Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009). Conclusions Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative). While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings. PMID:25478862

  11. 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.

  12. 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

  13. 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

    2014-10-01

    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.

  14. Quantitative analysis of peri-tumor tissue elasticity based on shear-wave elastography for breast tumor classification.

    PubMed

    Xiao, Yang; Zeng, Jie; Qian, Ming; Zheng, Rongqin; Zheng, Hairong

    2013-01-01

    For shear-wave elastography (SWE) images, the most common site of tumor-associated stiffness is generally in the surrounding stroma rather than the tumor itself. The aim of this study is to assess the value of the peri-tumor tissue elasticity in the classification of breast tumors. SWE images of 106 breast tumors (65 benign, 41 malignant) were collected from 82 consecutive patients. By applying the image processing method, 5 elastographic features of the peri-tumor area (elasticity modulus mean, maximum, standard deviation, hardness degree and elasticity ratio) were computed to represent peri-tumor tissue elasticity. B-mode Breast Imaging Reporting and Data System (BI-RADS) were used for comparing the diagnostic performances between the grayscale US and color SWE images. Histopathologic results were used as the reference standard. The t-test, point biserial correlation coefficient and receiver operating characteristic (ROC) curve analysis were performed for statistical analysis. As a result, the Az values (area under ROC curve) were 0.92, 0.95, 0.94, 0.91, and 0.98 for the classifiers using the five elastographic features respectively, and 0.91 for BI-RADS assessment. The results showed that the peri-tumor tissue elasticity could provide valuable information for breast tumor classification.

  15. Gene expression in local stroma reflects breast tumor states and predicts patient outcome

    PubMed Central

    Bainer, Russell; Frankenberger, Casey; Rabe, Daniel; An, Gary; Gilad, Yoav; Rosner, Marsha Rich

    2016-01-01

    The surrounding microenvironment has been implicated in the progression of breast tumors to metastasis. However, the degree to which metastatic breast tumors locally reprogram stromal cells as they disrupt tissue boundaries is not well understood. We used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in a panel of paired tumor and stroma tissues. We find that gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in stromal gene expression elicited by tumors better predicts subtype and patient survival than tumor gene expression, and genes with coordinated expression in both tissues predict metastasis-free survival. These observations support the use of stroma-based strategies for the diagnosis and prognosis of breast cancer. PMID:27982086

  16. [Malignant phyllode tumor of the breast with features of intraductal carcinoma].

    PubMed

    Alò, P L; Andreano, T; Monaco, S; Sebastiani, V; Eleuteri Serpieri, D; Di Tondo, U

    2001-04-01

    Malignant phyllode tumor is a rare biphasic breast tumor consisting of a malignant mesenchymal component and an epithelial component that is usually benign. We report an unusual case of a malignant phyllode tumor of the breast with neoplastic features of both the epithelial and stromal components. The patient was a 39-year-old woman with family history for breast carcinoma. Grossly, the excised tumor was a 9 x 7 x 5.5 cm gray lobulated mass with infiltrative margins and necrotic-hemorrhagic areas. Histologically the tumor consisted mainly of neoplastic mesenchyme with non invasive comedo, cribriform and micropapillary features of the ducts. Three months after the excision of the neoplastic mass, the patient developed an infiltrating ductal carcinoma of the opposite breast. Hereditary and bilateral tumors are commonly associated with germline mutations. Tissue from both neoplasms however did not express either BRCA1 or BRCA2 mutations.

  17. The role of quantitative estrogen receptor status in predicting tumor response at surgery in breast cancer patients treated with neoadjuvant chemotherapy.

    PubMed

    Raphael, Jacques; Gandhi, Sonal; Li, Nim; Lu, Fang-I; Trudeau, Maureen

    2017-07-01

    Estrogen receptor (ER) negative (-) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database "Biomatrix" to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3 months (Q1-Q3 28.7-61.1) and a mean age of 49.7 years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99-1.00, p = 0.027 and 0.98 95% CI 0.97-0.99, p < 0.0001, respectively). A cut-off of 60 and 80% predicted best the association with tumor size reduction and pCR, respectively. pCR was shown to be an independent predictor of RFS (HR 0.17, 95% CI 0.07-0.43, p = 0.0002) in all patients. At 5 years, 93% of patients with pCR and 72% of patients with residual tumor were recurrence-free, respectively (p = 0.0012). Quantitative ER status is inversely associated with tumor response in BC patients treated with NCT. A cut-off of 60 and 80% predicts best the association with tumor size reduction and pCR, respectively. Therefore, patients with an ER status higher than the cut-off might benefit from a neoadjuvant endocrine therapy approach. Patients with pCR had better survival outcomes independently of their tumor phenotype. Further prospective studies are needed to validate the clinical utility of quantitative ER as a predictive marker of tumor response.

  18. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    PubMed Central

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Objective Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Methods Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. Results 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. Conclusions These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast

  19. Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.

    PubMed

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and

  20. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells

    PubMed Central

    2011-01-01

    Introduction Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells. Methods Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model). Results Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. Conclusions Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition

  1. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells.

    PubMed

    Nair, Binoj C; Vallabhaneni, Sreeram; Tekmal, Rajeshwar R; Vadlamudi, Ratna K

    2011-08-11

    Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells. Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model). Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition of CDK2 activity has the potential to

  2. Is "prepectoral edema" a morphologic sign for malignant breast tumors?

    PubMed

    Kaiser, Clemens G; Herold, Michael; Baltzer, Pascal A T; Dietzel, Matthias; Krammer, Julia; Gajda, Mieczyslaw; Camara, Oumar; Schoenberg, Stefan O; Kaiser, Werner A; Wasser, Klaus

    2015-06-01

    A variety of morphologic and kinetic signs of benign or malignant breast lesions contribute to a final diagnosis and differential diagnosis in magnetic resonance (MR) mammography (MRM). As a new sign, prepectoral edema (PE) in patients without any history of previous biopsy, operation, radiation, or chemotherapy was detected during routine breast MR examinations. The purpose of this study was to retrospectively evaluate the role of this morphologic sign in the differential diagnosis of breast lesions. Between January 2005 and October 2006, a total of 1109 consecutive MRM examinations have been performed in our institution. In this study, only patients who would later be biopsied or operated in our own hospital were included. They had no previous operation, biopsy, intervention, chemotherapy, hormone replacement therapy, or previous mastitis. In total, 162 patients with 180 lesions were included, histologically correlated later-on by open biopsy (124 patients and 136 lesions) or core biopsy (38 patients and 44 lesions). The evaluations were performed by four experienced radiologists in consensus. One hundred eighty evaluated lesions included 104 malignant lesions (93 invasive and 11 noninvasive cancers) and 76 benign lesions. PE was detected in 2.6% of benign lesions (2 of 76), in none of the Ductal cacinoma in situ (DCIS) cases (0 of 11), and in 25.8% of malignant lesions (24 of 93; P < .000). PE was found significantly more frequently in presence of malignant tumors >2 cm in diameter (48.5%, 17 of 35 vs. 13.8%, 8 of 58; P < .001). PE was not statistically associated to malignant tumor type, presence or absence of additional DCIS, and number of lesions. This resulted in the following diagnostic parameters for PE as an indicator for malignancy: sensitivity of 19.3%, specificity of 97.3%, positive predictive value (PPV) of 92.3%, negative predictive value of 48%, and accuracy of 57.7%. In case of occurrence, the "PE sign" seems to be a specific indicator for

  3. [Common benign breast tumors including fibroadenoma, phyllodes tumors, and papillary lesions: Guidelines].

    PubMed

    Bendifallah, S; Canlorbe, G

    2015-12-01

    To provide guidelines for clinical practice from the French College of Obstetrics and Gynecology (CNGOF), based on the best evidence available, concerning common benign breast tumors: fibroadenoma (FA), phyllodes breast tumors (PBT), and papillary lesions (BPL). Bibliographical search in French and English languages by consultation of PubMed, Cochrane and international databases. In case of percutaneous biopsy diagnosis of FA, clinico-radiologic and pathologic discordance or complex FA or proliferative lesions or atypia with FA, a family history of cancer, it seems legitimate to discuss management in a multidisciplinary meeting. When surgery is proposed for FA, periareolar compared to direct incision is associated with more insensitive nipple but better aesthetic results (LE4). When surgery is proposed for FA, indirect incision is preferable for better cosmetic results (Grade C). Techniques of percutaneous destruction or resection can be used (Grade C). The WHO classification distinguishes three categories of phyllodes tumors (PBT): benign (grade 1), borderline (grade 2) and malignant (grade 3). For grade 1 PBT, the risk of local recurrence after surgical excision increases when PBT lesion is in contact with surgical limits (not in sano). After in sano resection, there is no correlation between margin size and the risk of recurrence (LE4). For grade 2 PBT, local recurrence after surgical excision increases for margins under 10mm margins (LE4). For grade 1-2 PBT, in sano excision is recommended. For grade 2 PBT, 10-mm margins are recommended (Grade C). No lymph node evaluation or neither systematic mastectomy is recommended (Grade C). Breast papillary lesion (BPL) without atypia, complete resection of radiologic signal is recommended (Grade C). For BPL with atypia, complete excisional surgery is recommended (Grade C). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. Dynamic thermal modeling of the normal and tumorous breast under elastic deformation.

    PubMed

    Jiang, Li; Zhan, Wang; Loew, Murray H

    2008-01-01

    To quantify the complex relationships between (1) the temperature, and temperature differences, on the surface of the breast as recorded by infrared thermal imaging and (2) the underlying physiological and pathological factors, we have developed a dynamic finite element method for comprehensive modeling of both the thermal and elastic properties of normal and tumorous breast tissues. In the steady state, the gravity-induced deformation is found to cause markedly asymmetric surface temperatures even though all thermal-elastic properties are symmetrical. In the dynamic state, the time course of breast thermal imaging in cold-stress and thermal-recovery procedures is found to be useful in characterizing the origins of the thermal contrast on the breast surface. The tumor-induced thermal contrast has slower temporal behavior than the deformation-induced thermal contrast on the breast surface, which may lead to improvements in breast-tumor diagnosis.

  5. miRNA expression profiling of formalin-fixed paraffin-embedded (FFPE) hereditary breast tumors

    PubMed Central

    Tanić, Miljana; Yanowski, Kira; Andrés, Eduardo; Gómez-López, Gonzalo; Socorro, María Rodríguez-Pinilla; Pisano, David G.; Martinez-Delgado, Beatriz; Benítez, Javier

    2014-01-01

    Hereditary breast cancer constitutes only 5–10% of all breast cancer cases and is characterized by strong family history of breast and/or other associated cancer types. Only ~ 25% of hereditary breast cancer cases carry a mutation in BRCA1 or BRCA2 gene, while mutations in other rare high and moderate-risk genes and common low penetrance variants may account for additional 20% of the cases. Thus the majority of cases are still unaccounted for and designated as BRCAX tumors. MicroRNAs are small non-coding RNAs that play important roles as regulators of gene expression and are deregulated in cancer. To characterize hereditary breast tumors based on their miRNA expression profiles we performed global microarray miRNA expression profiling on a retrospective cohort of 80 FFPE breast tissues, including 66 hereditary breast tumors (13 BRCA1, 10 BRCA2 and 43 BRCAX), 10 sporadic breast carcinomas and 4 normal breast tissues, using Exiqon miRCURY LNA™ microRNA Array v.11.0. Here we describe in detail the miRNA microarray expression data and tumor samples used for the study of BRCAX tumor heterogeneity (Tanic et al., 2013) and biomarkers associated with positive BRCA1/2 mutation status (Tanic et al., 2014). Additionally, we provide the R code for data preprocessing and quality control. PMID:26484152

  6. 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

  7. 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

  8. Granular Cell Tumor of Breast: a Case Report and Review of Literature.

    PubMed

    Rexeena, Bhargavan; Paul, Augustine; Nitish, Ranjan Acharya; Kurian, Cherian; Anila, R K

    2015-12-01

    This is an article reporting a case of granular cell tumor in the left breast in a 58 year old lady. Patient presented with a 3 × 3 cm mass in the left breast. Mammography reported a BIRADS 5 lesion in the left breast. With a clinical and radiological diagnosis of malignancy, patient was sent for FNAC (Fine needle aspiration Cytology). The cytology report was granular cell tumor. Following this patient underwent wide excision of the mass. Histopathology confirmed the cytological diagnosis of granular cell tumor of the breast. Patient is on regular follow up and is presently free of disease. The case report is followed up by a brief review of literature of granular cell tumor of the breast.

  9. Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors

    PubMed Central

    Creighton, Chad J; Cordero, Kevin E; Larios, Jose M; Miller, Rebecca S; Johnson, Michael D; Chinnaiyan, Arul M; Lippman, Marc E; Rae, James M

    2006-01-01

    Background Estrogen plays a central role in breast cancer pathogenesis. Although many studies have characterized the estrogen regulation of genes using in vitro cell culture models by global mRNA expression profiling, it is not clear whether these genes are similarly regulated in vivo or how they might be coordinately expressed in primary human tumors. Results We generated DNA microarray-based gene expression profiles from three estrogen receptor α (ERα)-positive breast cancer cell lines stimulated by 17β-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. When the patterns of genes regulated by E2 in vitro were compared to those obtained from xenografts, we found a remarkable overlap (over 40%) of genes regulated by E2 in both contexts. These patterns were compared to those obtained from published clinical data sets. We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERα in a panel of ERα+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor. Furthermore, the E2-regulated genes were significantly enriched for transcriptional targets of the myc oncogene and were found to be coordinately expressed with Myc in human tumors. Conclusion Our results provide significant validation of a widely used in vitro model of estrogen signaling as being pathologically relevant to breast cancers in vivo. PMID:16606439

  10. Tumor STAT1 transcription factor activity enhances breast tumor growth and immune suppression mediated by myeloid-derived suppressor cells.

    PubMed

    Hix, Laura M; Karavitis, John; Khan, Mohammad W; Shi, Yihui H; Khazaie, Khashayarsha; Zhang, Ming

    2013-04-26

    Previous studies had implicated the IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33(+) myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.

  11. 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.

  12. MMP13 is potentially a new tumor marker for breast cancer diagnosis.

    PubMed

    Chang, Hui-Jen; Yang, Ming-Je; Yang, Yu-Hsiang; Hou, Ming-Feng; Hsueh, Er-Jung; Lin, Shiu-Ru

    2009-11-01

    Within the past decade, the incidence of breast cancer in Taiwan has been rising year after year. Breast cancer is the first most prevalent cancer and the fourth leading cause of cancer-related deaths among women in Taiwan. The early stage of breast cancer not only have a wider range of therapeutic options, but also obtain a higher success rate of therapy than those with advanced breast cancer. A test for tumor markers is the most convenient method to screen for breast cancer. However, the tumor markers currently available for breast cancer detection include carcinoembryonic antigen (CEA), carbohydrate antigen 15.3 (CA15.3), and carbohydrate antigen 27.29 (CA27.29) exhibited certain limitations. Poor sensitivity and specificity greatly limits the diagnostic accuracy of these markers. This study aims to identify potential tumor markers for breast cancer. At first, we analyzed genes expression in infiltrating lobular carcinoma, metaplastic carcinoma, and infiltrating ductal carcinoma of paired specimens (tumor and normal tissue) from breast cancer patients using microarray technology. We selected 371 overexpressed genes in all of the three cell type. In advanced breast cancer tissue, we detected four genes MMP13, CAMP, COL10A1 and FLJ25416 from 25 overexpressed genes which encoded secretion protein more specifically for breast cancer than other genes. After validation with 15 pairs of breast cancer tissue and paired to normal adjacent tissues by membrane array and quantitative RT-PCR, we found MMP13 was 100% overexpressed and confirmed to be a secreted protein by Western blot analysis of the cell culture medium. The expression level of MMP13 was also measured by immunohistochemical staining. We suggest that MMP13 is a highly overexpressed secretion protein in breast cancer tissue. It has potential to be a new tumor marker for breast cancer diagnosis.

  13. An approach to parameter estimation for breast tumor by finite element method

    NASA Astrophysics Data System (ADS)

    Xu, A.-qing; Yang, Hong-qin; Ye, Zhen; Su, Yi-ming; Xie, Shu-sen

    2009-02-01

    The temperature of human body on the surface of the skin depends on the metabolic activity, the blood flow, and the temperature of the surroundings. Any abnormality in the tissue, such as the presence of a tumor, alters the normal temperature on the skin surface due to increased metabolic activity of the tumor. Therefore, abnormal skin temperature profiles are an indication of diseases such as tumor or cancer. This study is to present an approach to detect the female breast tumor and its related parameter estimations by combination the finite element method with infrared thermography for the surface temperature profile. A 2D simplified breast embedded a tumor model based on the female breast anatomical structure and physiological characteristics was first established, and then finite element method was used to analyze the heat diffuse equation for the surface temperature profiles of the breast. The genetic optimization algorithm was used to estimate the tumor parameters such as depth, size and blood perfusion by minimizing a fitness function involving the temperature profiles simulated data by finite element method to the experimental data obtained by infrared thermography. This preliminary study shows it is possible to determine the depth and the heat generation rate of the breast tumor by using infrared thermography and the optimization analysis, which may play an important role in the female breast healthcare and diseases evaluation or early detection. In order to develop the proposed methodology to be used in clinical, more accurate anatomy 3D breast geometry should be considered in further investigations.

  14. A Case of Large Phyllodes Tumor Causing “Rupture” of the Breast: A Unique Presentation

    PubMed Central

    Nabi, Junaid; Akhter, S. M. Quamrul; Authoy, Fatema N.

    2013-01-01

    Introduction. Phyllodes tumors are rare fibroepithelial tumors which constitute less than 1% of all known breast neoplasms. The importance of recognizing these tumors lies in the need to differentiate them from fibroadenomas and other benign breast lesions to avoid inappropriate surgical management. We report a case of large phyllodes tumor which caused rupture of the breast and presented as an external fungating breast mass, a presentation which is exceedingly rare. Case Presentation. A 32-year-old female presented with a 1-year history of a mass in her right breast and eruption of the mass through the skin for the last 3 months. On physical examination, an ulcerated, irregular, and nodular mass measuring 9 × 8 cms was found hanging in the lower and outer quadrant of the right breast. Ultrasonography revealed an exophytic mass with heterogeneous echotexture and vascularity. Under general anesthesia, the tumor was excised. The resected specimen was 9.5 × 8.5 × 4.5 cm in size and the tumor was not invasive to the surrounding tissues. Histological examination confirmed a benign case of Phyllodes tumor. Conclusion. Clinicians should be aware of the myriad ways in which Phyllodes can present. A rapidly growing breast mass in a female should raise strong suspicion for Phyllodes. It is necessary to differentiate it from fibroadenomas to avoid inappropriate surgical management which may lead to local recurrence. PMID:23762692

  15. Multiplexed ion beam imaging of human breast tumors.

    PubMed

    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

    2014-04-01

    Immunohistochemistry (IHC) is a tool for visualizing protein expression that is employed as part of the diagnostic workup 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 human breast tumor tissue sections stained with ten labels simultaneously. The resulting data suggest that MIBI can provide new insights into disease pathogenesis that will be valuable for basic research, drug discovery and clinical diagnostics.

  16. Hormone Receptor and ERBB2 Status in Gene Expression Profiles of Human Breast Tumor Samples

    PubMed Central

    Dvorkin-Gheva, Anna; Hassell, John A.

    2011-01-01

    The occurrence of large publically available repositories of human breast tumor gene expression profiles provides an important resource to discover new breast cancer biomarkers and therapeutic targets. For example, knowledge of the expression of the estrogen and progesterone hormone receptors (ER and PR), and that of the ERBB2 in breast tumor samples enables choice of therapies for the breast cancer patients that express these proteins. Identifying new biomarkers and therapeutic agents affecting the activity of signaling pathways regulated by the hormone receptors or ERBB2 might be accelerated by knowledge of their expression levels in large gene expression profiling data sets. Unfortunately, the status of these receptors is not invariably reported in public databases of breast tumor gene expression profiles. Attempts have been made to employ a single probe set to identify ER, PR and ERBB2 status, but the specificity or sensitivity of their prediction is low. We enquired whether estimation of ER, PR and ERBB2 status of profiled tumor samples could be improved by using multiple probe sets representing these three genes and others with related expression. We used 8 independent datasets of human breast tumor samples to define gene expression signatures comprising 24, 51 and 14 genes predictive of ER, PR and ERBB2 status respectively. These signatures, as demonstrated by sensitivity and specificity measures, reliably identified hormone receptor and ERBB2 expression in breast tumors that had been previously determined using protein and DNA based assays. Our findings demonstrate that gene signatures can be identified which reliably predict the expression status of the estrogen and progesterone hormone receptors and that of ERBB2 in publically available gene expression profiles of breast tumor samples. Using these signatures to query transcript profiles of breast tumor specimens may enable discovery of new biomarkers and therapeutic targets for particular subtypes of

  17. Breast tumor subgroups reveal diverse clinical prognostic power

    PubMed Central

    Liu, Zhaoqi; Zhang, Xiang-Sun; Zhang, Shihua

    2014-01-01

    Predicting the outcome of cancer therapies using molecular features and clinical observations is a key goal of cancer biology, which has been addressed comprehensively using whole patient datasets without considering the effect of tumor heterogeneity. We hypothesized that molecular features and clinical observations have different prognostic abilities for different cancer subtypes, and made a systematic study using both clinical observations and gene expression data. This analysis revealed that (1) gene expression profiles and clinical features show different prognostic power for the five breast cancer subtypes; (2) gene expression data of the normal-like subgroup contains more valuable prognostic information and survival associated contexts than the other subtypes, and the patient survival time of the normal-like subtype is more predictable based on the gene expression profiles; and (3) the prognostic power of many previously reported breast cancer gene signatures increased in the normal-like subtype and reduced in the other subtypes compared with that in the whole sample set. PMID:24499868

  18. The Relationship between Bone Mineral Density and Estrogen Receptor Positivity in Patients with Breast Cancer

    PubMed Central

    İyigün, Zeynep Erdoğan; Pilancı, Kezban Nur; Çabuk, Fatmagül Kuşku; İlgün, Serkan; Ordu, Çetin; Duymaz, Tomris; Alço, Gül; Çelebi, Filiz; Sarsenov, Dauren; İzci, Filiz; Öztürk, Alper; Ağaçayak, Filiz; Köksal, Ülkühan İner; Aktepe, Fatma; Eralp, Yeşim; Özmen, Vahit

    2016-01-01

    Objective The effect of estrogen on bone mineral density (BMD) and breast cancer has been known for a long time. The aim of this study was to compare of the BMD of patients with breast cancer and healthy individuals, and to investigate the degree of correlation of estrogen receptor (ER) with BMD. Materials and Methods Seventy-one patients with postmenopausal breast cancer and 79 healthy dividuals were included in the study. The patient demographics (age, menopause age, body mass index, number of children, BMD, Z scores, and estrogen status for breast cancer patients) were taken from hospital records. Results No significant difference was detected between the case and control groups in lumbar region Z scores (p=0.074). At the femur neck, the control group Z scores was higher than patient group (p=0.002). BMI was higher in the patients with breast cancer (p=0.001). There was no statistically significant correlation between ER positivity, BMD, and BMI in ER-positive patients (p=0.495, p=0.8, p=0.846, respectively). There was no difference between the Z scores when the patients were divided into two groups as ER positive and negative (p=0.156, p=0.335, respectively). Conclusion This study revealed that there is no difference in lumbar region Z scores between patients with breast cancer and heathy controls; however, the Z scores were higher in the femur neck in the control group, and the BMI was lower in the patient group. Tumor ER positivity does not positively affect BMD.

  19. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors.

    PubMed

    Cho, Robert W; Wang, Xinhao; Diehn, Maximilian; Shedden, Kerby; Chen, Grace Y; Sherlock, Gavin; Gurney, Austin; Lewicki, John; Clarke, Michael F

    2008-02-01

    In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells.

  20. 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. |

  1. 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 ...

  2. Metastatic carcinoid tumor to the breast: report of two cases and review of the literature.

    PubMed

    Lee, Shimwoo; Levine, Pascale; Heller, Samantha L; Hernandez, Osvaldo; Mercado, Cecilia L; Chhor, Chloe M

    The breast is an unusual site for carcinoid metastasis. Due to increasing survival rates for carcinoid tumors, however, awareness of their rare complications is important. Carcinoid metastasis to the breast typically presents as a palpable breast mass or a mass on screening mammogram. Because imaging findings are nonspecific, the diagnosis is established through histological findings of neuroendocrine features corresponding with the known primary carcinoid pathology. Correctly distinguishing metastatic carcinoid from primary breast carcinoma is crucial to avoid more invasive procedures required for the latter. Two cases of metastatic carcinoid to the breast are presented with review of the literature. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Loss of B-cell translocation gene 2 expression in estrogen receptor-positive breast cancer predicts tamoxifen resistance

    PubMed Central

    Takahashi, Maiko; Hayashida, Tetsu; Okazaki, Hiroshi; Miyao, Kazuhiro; Jinno, Hiromitsu; Kitagawa, Yuko

    2014-01-01

    B-cell translocation gene 2 (BTG2), a gene suppressed in a subset of aggressive breast cancer, is repressed by estrogen. BTG2 inhibits the expression of HER ligands and promotes AKT activation, which plays an essential role in the tamoxifen resistance of estrogen receptor (ER)-positive breast cancer. To determine if BTG2 expression modifies tamoxifen efficacy, a cohort of 60 patients treated with adjuvant tamoxifen monotherapy was analyzed. We found that increased BTG2 expression showed better clinical survival and was the only independent prognostic factor for disease-free survival (hazard ratio, 0.691; 95% confidence interval, 0.495–0.963; P = 0.029). Tamoxifen suppressed the human epidermal growth factor receptor 2 (HER2)-Akt signaling in BTG2 expressing ER-positive breast cancer cells with a correlated increase in sensitivity, whereas BTG2 knockdown abrogated this sensitivity. Consistent with this observation, tamoxifen significantly suppressed the growth ratio, tumor weight and Ki-67 expression in BTG2 expressing breast cancer xenografts in mice. These studies demonstrate that BTG2 is a significant factor in tamoxifen response, acting through modification of AKT activation in ER-positive/HER2-negative breast cancer. PMID:24698107

  4. Endocrine disruptors and the tumor microenvironment: A new paradigm in breast cancer biology.

    PubMed

    Burks, Hope; Pashos, Nicholas; Martin, Elizabeth; Mclachlan, John; Bunnell, Bruce; Burow, Matthew

    2017-12-05

    Breast cancer is one of the most frequently diagnosed malignancies in women and is characterized by predominantly estrogen dependent growth. Endocrine disruptors (EDCs) have estrogenic properties which have been shown to increase breast cancer risk. While the direct effects of EDCs on breast cancer cell biology and tumor progression have been well studied, the roles for EDCs on tumor microenvironment composition, signaling and structure are incompletely defined. Estrogen targeting of tumor stromal cells can drive paracrine signaling to breast cancer cells regulating tumorigenesis and progression. Additionally, estrogen and estrogen receptor signaling has been shown to alter breast architecture and extracellular matrix component synthesis. Unsurprisingly, EDCs have been shown to induce structural changes in the mammary gland as well as increased collagen fibers in the tissue stroma. Previous work demonstrates that human mesenchymal stem cells (hMSC) are essential components of the tumor microenvironment and are direct targets of both estrogens and EDCs. Furthermore, estrogen-stem cell cross talk has been implicated in breast cancer progression and results in increased tumor cell proliferation, angiogenesis and invasion. This review aims to dissect the possible relationship and mechanisms between EDCs, the tumor microenvironment, and breast cancer progression. Copyright © 2016. Published by Elsevier B.V.

  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. Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors.

    PubMed

    Ellsworth, Rachel E; Hooke, Jeffrey A; Love, Brad; Kane, Jennifer L; Patney, Heather L; Ellsworth, Darrell L; Shriver, Craig D

    2008-01-01

    Pathological grade is a useful prognostic factor for stratifying breast cancer patients into favorable (well-differentiated tumors) and less favorable (poorly-differentiated tumors) outcome groups. The current system of tumor grading, however, is subjective and a large proportion of tumors are characterized as intermediate-grade tumors, making determination of optimal treatments difficult. To determine whether molecular profiles can discriminate breast disease by grade, patterns and levels of allelic imbalance (AI) at 26 chromosomal regions frequently altered in breast disease were examined in 185 laser microdissected specimens representing well-differentiated (grade 1; n = 55), moderately-differentiated (grade 2; n = 71), and poorly-differentiated (grade 3; n = 59) stage I-IV breast tumors. Overall levels of AI were significantly higher in grade 3 compared to grade 1 tumors (P < 0.05). Grades 1 and 3 showed distinct genetic profiles--grade 1 tumors were associated with large deletions of chromosome 16q22, while alterations at 9p21, 11q23, 13q14, 17p13.1 and 17q12 were characteristics of grade 3 carcinomas. In general, levels and patterns of AI in grade 2 carcinomas were intermediate between grade 1 and grade 3 tumors. Patterns of AI accurately categorized approximately 70% of samples into high- or low-grade disease groups, suggesting that the majority of breast tumors have genetic profiles consistent with high- or low-grade, and that molecular signatures of breast tumors can be useful for more accurate characterization of invasive breast cancer.

  7. 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

  8. Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

    PubMed

    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.

  9. Cell surface profiling with peptide libraries yields ligand arrays that classify breast tumor subtypes.

    PubMed

    Dane, Karen Y; Gottstein, Claudia; Daugherty, Patrick S

    2009-05-01

    Cancer heterogeneity renders risk stratification and therapy decisions challenging. Thus, genomic and proteomic methodologies have been used in an effort to identify biomarkers that can differentiate tumor subtypes to improve therapeutic outcome. Here, we report a generally applicable strategy to generate tumor type-specific peptide ligand arrays. Peptides that specifically recognize breast tumor-derived cell lines (MDA-MB-231, MCF-7, and T47-D) were identified using cell-displayed peptide libraries carrying an intrinsic fluorescent marker allowing for sorting and characterization with quantitative flow cytometry. Tumor cell specificity was achieved by depleting libraries of ligands binding to normal mammary epithelial cells (HMEC and MCF-10A). Although integrin binding RGD motifs were favored by some cell lines, screening with RGD competitors yielded several novel consensus motifs exhibiting improved tumor specificity. The resultant peptide array contained multiple consensus motifs exhibiting strong similarity to breast tumor-associated proteins. Profiling a panel of breast cancer cell lines with the peptide array revealed receptor expression patterns distinctive for luminal or basal tumor subtypes. In addition, peptide displaying bacteria and peptide functionalized microparticles enabled fluorescent labeling of tumor cells and frozen tumor tissue sections. Our results indicate that cell surface profiling using highly specific breast tumor cell binding ligands may provide an efficient route for tumor subtype classification, biomarker identification, and for the development of targeted diagnostics and therapeutics.

  10. 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

  11. 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.

  12. 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.

  13. Anemia and jejunal intussusception: An unusual presentation for a metastatic phyllodes breast tumor.

    PubMed

    Schechet, Sidney A; Askenasy, Erik P; Dhamne, Sagar; Scott, Bradford G

    2012-01-01

    Phyllodes tumor of the breast is a rare cause of breast cancer, accounting for less than 0.5% of breast cancers. These tumors are classified as benign, borderline, or malignant, with malignant tumors compromising nearly 25% of cases. Metastases occur in 20% of malignant tumors, lungs, bones, liver and brain being the frequent sites of metastases. We present a case of a metastatic phyllodes tumor to the small bowel causing jejunal intussusception, symptomatic anemia, and small bowel obstruction. Patients with phyllodes tumor of the breast can develop disease recurrence even years after initial treatment. Phyllodes tumor metastasizing to the small bowel is extremely rare, with only three known previously described case reports in the literature. High risk patients, with a past medical history of phyllodes breast cancer, should be monitored closely. Even years after breast cancer treatment, these patients may present with gastrointestinal complaints such as obstruction or bleeding, and therefore metastatic disease to the small bowel should be considered on the differential with subsequent abdominal imaging obtained.

  14. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer

    PubMed Central

    Hallett, Robin M.; Girgis-Gabardo, Adele; Gwynne, William D.; Giacomelli, Andrew O.; Bisson, Jennifer N.P.; Jensen, Jeremy E.; Dvorkin-Gheva, Anna; Hassell, John A.

    2016-01-01

    Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions. PMID:27447971

  15. Anemia and jejunal intussusception: An unusual presentation for a metastatic phyllodes breast tumor

    PubMed Central

    Schechet, Sidney A.; Askenasy, Erik P.; Dhamne, Sagar; Scott, Bradford G.

    2011-01-01

    INTRODUCTION Phyllodes tumor of the breast is a rare cause of breast cancer, accounting for less than 0.5% of breast cancers. These tumors are classified as benign, borderline, or malignant, with malignant tumors compromising nearly 25% of cases. Metastases occur in 20% of malignant tumors, lungs, bones, liver and brain being the frequent sites of metastases. PRESENTATION OF CASE We present a case of a metastatic phyllodes tumor to the small bowel causing jejunal intussusception, symptomatic anemia, and small bowel obstruction. DISCUSSION Patients with phyllodes tumor of the breast can develop disease recurrence even years after initial treatment. Phyllodes tumor metastasizing to the small bowel is extremely rare, with only three known previously described case reports in the literature. CONCLUSION High risk patients, with a past medical history of phyllodes breast cancer, should be monitored closely. Even years after breast cancer treatment, these patients may present with gastrointestinal complaints such as obstruction or bleeding, and therefore metastatic disease to the small bowel should be considered on the differential with subsequent abdominal imaging obtained. PMID:22288047

  16. 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.

  17. Evaluation of an interactive ultrasound-based breast tumor contouring workflow

    NASA Astrophysics Data System (ADS)

    Mair, Aniqah T.; Vaughan, Thomas A.; Ungi, Tamas; Lasso, Andras; Engel, C. Jay; Rudan, John R.; Fichtinger, Gabor

    2017-03-01

    PURPOSE: Computer-navigated breast tumor excision using tracked ultrasound is a technique for performing lumpectomies during early-stage breast cancer. An interactive method is used to contour tumors intra-operatively for excision. We evaluated this method's effectiveness in contouring the entire tumor with minimal inclusion of healthy tissue in the excision volume. Additionally, we investigated the possibility of adding a safety margin to the contoured volume to ensure that the entire tumor is contained by the contour. METHODS: We conducted a study in which 10 participants contoured 5 tumors each using the intra-operative breast tumor contouring system. We analyzed their interactions with the system and their opinions of the contouring workflow. RESULTS: We found that only 0.19% of the tumor volume was not contained by the contour on average. The addition of a 0.4 mm safety margin to the final tumor contour guaranteed that the entire tumor would be contained. We also found a correlation between the amount of time spent on contour verification and excess healthy tissue included in the contour. Users' perceptions of how well they excluded excess healthy tissue strongly correlated with reality. CONCLUSIONS: This workflow ensures that only a small amount of tumor volume is not contained by the contour and allows the radiologist confidence that they have contained the entire tumor in their contour. With the addition of a safety margin to the resulting tumor contour, the tumor can be completely contained.

  18. AR Signaling in Breast Cancer

    PubMed Central

    Rahim, Bilal; O’Regan, Ruth

    2017-01-01

    Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies. PMID:28245550

  19. AR Signaling in Breast Cancer.

    PubMed

    Rahim, Bilal; O'Regan, Ruth

    2017-02-24

    Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

  20. Inhibition of primary breast tumor growth and metastasis using a neuropilin-1 transmembrane domain interfering peptide

    PubMed Central

    Arpel, Alexia; Gamper, Coralie; Spenlé, Caroline; Fernandez, Aurore; Jacob, Laurent; Baumlin, Nadège; Laquerriere, Patrice; Orend, Gertraud; Crémel, Gérard; Bagnard, Dominique

    2016-01-01

    The transmembrane domains (TMD) in membrane receptors play a key role in cell signaling. As previously shown by us a peptide targeting the TMD of neuropilin-1 (MTP-NRP1), blocks cell proliferation, cell migration and angiogenesis in vitro, and decreases glioblastoma growth in vivo. We now explored the clinical potential of MTP-NRP1 on breast cancer models and demonstrate that MTP-NRP1 blocks proliferation of several breast cancer lines including the MDA-MB-231, a triple negative human breast cancer cell line. In models with long term in vivo administration of the peptide, MTP-NRP1 not only reduced tumor volume but also decreased number and size of breast cancer metastases. Strikingly, treating mice before tumors developed protected from metastasis establishment/formation. Overall, our results report that targeting the TMD of NRP1 in breast cancer is a potent new strategy to fight against breast cancer and related metastasis. PMID:27351129

  1. 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

  2. Tamoxifen Action in ER-Negative Breast Cancer.

    PubMed

    Manna, Subrata; Holz, Marina K

    2016-02-10

    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.

  3. 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

  4. Male breast cancer according to tumor subtype and race: a population based study

    PubMed Central

    Chavez-MacGregor, Mariana; Clarke, Christina A.; Lichtensztajn, Daphne; Hortobagyi, Gabriel N.; Giordano, Sharon H.

    2014-01-01

    Background Breast cancer occurs rarely in men. To the best of our knowledge, there are no population-based estimates of the incidence of HER2-neu-positive breast cancer or of the distribution of breast cancer subtypes among male patients. We explored breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California. Methods We included male breast cancer patients diagnosed with invasive breast cancer between 2005-2009 with known ER, PR and HER2-neu status reported to the California Cancer Registry. Among the patients with hormone receptor (HR)-positive tumors, survival probabilities between groups were compared using log-rank tests. Results Six-hundred and six patients were included. Median age at diagnosis was 68 years. Four hundred and ninety four (81.5%) patients had HR+ tumors, defined as ER+ and/or PR+ and HER2-negative. Ninety (14.9%) had HER2-neu-positive, and 22 (3.6%) had triple receptor-negative tumors (TN). Among HR+ patients, Non-Hispanic Blacks and Hispanics were more likely to have PR negative tumors compared to Non-Hispanic Whites. There was a borderline statistically significant difference in survival according to tumor subtype (p=0.088). Differences in survival according to race/ethnicity were seen among all patients (p=0.087) and among those with HR+ tumors (p=0.0170), with Non-Hispanic Blacks having poorer outcomes. Conclusions In this large, representative cohort of male breast cancer patients, the distribution of tumor subtypes was different from that reported for females and varied by race/ethnicity. Non-Hispanic Blacks were more likely to have triple receptor-negative tumors and more likely to have ER+/PR- tumors than white men. PMID:23341341

  5. 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.

  6. 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.

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

    PubMed Central

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

    2015-01-01

    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

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

    PubMed

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

    2015-05-05

    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.

  9. [Non-invasive detection of the boundary of early breast tumor using DSF-DOT].

    PubMed

    Cui, Weipan; Zhang, Hang; Luo, Bin; Xu, Jiangfeng

    2004-12-01

    Traditional biomedical imaging technology has a difficulty in detecting the boundary of a breast tumor at its early stage since the difference in the sound resistance or density between the early breast tumor and normal tissue is small. In this paper, the boundary of an early breast tumor is detected successfully by using a new method called DSF-DOT (delta sound field diffusion optical tomography), which is based on a sound field and the light diffusion theory. At the same time, the influence of the size of the acting area of the sound field on the reconstruction of the tumor boundary is investigated in details. The work is useful for further research on the diagnosis of early breast cancers.

  10. 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

  11. Poland syndrome and breast tumor: a case report and review of the literature.

    PubMed

    Mojallal, Ali; La Marca, Sophie; Shipkov, Christo; Sinna, Raphael; Braye, Fabienne

    2012-01-01

    Poland syndrome is a rare congenital malformation. Hypoplasia of the sternocostal portion of the pectoralis major muscle is the most significant feature and is most frequently associated with homolateral breast hypoplasia. In this article, the authors present a case of bilateral phyllodes tumors in a 28-year-old woman with Poland syndrome and discuss (1) the relationship between the condition and breast cancer, (2) the modes of surveillance in patients with Poland syndrome, and (3) its impact on breast reconstruction.

  12. Targeting MUC1 mediated tumor stromal metabolic interaction in Triple negative Breast Cancer

    DTIC Science & Technology

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0315 TITLE: Targeting MUC1-mediated tumor-stromal metabolic interaction in Triple- negative breast cancer PRINCIPAL...interaction in Triple-negative Breast Cancer 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Pankaj Singh, PhD 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail...overexpressed in TNBC and facilitates growth and metastasis of triple negative breast cancer (TNBC) cells. This occurrence can be partially attributed

  13. A study of tumor heterogeneity in a case with breast cancer.

    PubMed

    Nakada, Haruka; Nakagomi, Hiroshi; Hirotsu, Yosuke; Amemiya, Kenji; Mochizuki, Hitoshi; Inoue, Masayuki; Oyama, Toshio; Omata, Masao

    2017-05-01

    Tumor heterogeneity has been suggested based on clinical and pathological findings. Several clinical findings can be explained by tumor evolution during progression and metastasis. We herein report a case of metastatic breast cancer indicated tumor heterogeneity by clinical findings and a genomic analysis. A 64-year-old woman with advanced breast cancer was treated with primary chemotherapy, to which primary tumor responded. After a 6 month treatment pause, lung, liver, and skin metastases developed and her serum tumor markers were elevated. None of those serum markers had been elevated before the treatment, despite the large tumor burden. Notably, there was discordance in the expression of human epidermal growth factor receptor 2 (HER2) between the primary tumor and metastatic skin lesions, with the former being negative and the latter positive. A genomic analysis was performed by in-house Breast Cancer Panel, which consisted of 53 pre-selected genes. Twenty-three somatic mutations were found in primary breast tumor and 7 in the skin metastasis. None of these 30 genes matched. However, the cell-free (cf) DNA in the plasma taken at the time of skin metastasis contained 10 mutations, 7 from the primary lesion and 3 from the metastasis. These data indicate that the clonal changes or tumor heterogeneity was shown in two solid tumors by clinical and the result of a genomic analysis. Of particular interest was that cell-free DNA could be a powerful tool to look into these dynamic changes.

  14. Tumor Genomic Profiling in Breast Cancer Patients Using Targeted Massively Parallel Sequencing

    DTIC Science & Technology

    2015-04-30

    Total Number of Breast Tumors Total Number of ER+ Tumors Stephens et al1 100 primary tumors 79 ER+ primary tumors Banerji et al2 108 primary...Garraway LA, Yelensky R, Stephens PJ, Miller VA, Schlegel R, Quadt C, Baselga J. Towards defining the genetic 14 framework for clinical response to...Exploratory Research Consortium. 11. REFERENCES: 1. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela

  15. Macrophage Polarization: Anti-cancer Strategies to Target Tumor-associated Macrophage in Breast Cancer.

    PubMed

    Tariq, Muhammad; Zhang, Jieqiong; Liang, Guikai; Ding, Ling; He, Qiaojun; Yang, Bo

    2017-01-20

    Tumor-associated macrophages (TAMs) are the most abundant inflammatory cells and orchestrate different stages of breast cancer development. TAMs participate in the tumor angiogenesis, matrix remodeling, invasion, immunosuppression, metastasis, and chemoresistance in breast cancer. Several clinical studies indicate the association between the high influx of TAMs in tumor with poor prognosis in hepatocellular, ovarian, cervical, and breast cancer. Previously developed hypotheses have proposed that TAMs participate in antitumor responses of the body, while recently many clinical and experimental studies have revealed that TAMs in tumor microenvironment predominantly resemble with M2-like polarized macrophages and produce a high amount of anti-inflammatory factors which are directly responsible for the development of tumor. Various studies have shown that TAMs in tumor either enhance or antagonize the anti-tumor efficacy of cytotoxic agents, antibodies-targeting cancer cells, and therapeutic agents depending on the nature of treatment. Thereby, multiple roles of TAMs suggests that it is very important to develop novel therapeutic strategies to target TAMs in breast tumor. In this review, we have discussed the functional role of TAMs in breast cancer and summarized available recent advances potential therapeutic strategies that effectively target to TAMs cells. This article is protected by copyright. All rights reserved.

  16. 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

  17. Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages

    PubMed Central

    Smirnova, Tatiana; Bonapace, Laura; MacDonald, Gwen; Kondo, Shunya; Wyckoff, Jeffrey; Ebersbach, Hilmar; Fayard, Bérengère; Doelemeyer, Arno; Coissieux, Marie-May; Heideman, Marinus R.; Bentires-Alj, Mohamed; Hynes, Nancy E.

    2016-01-01

    The extracellular serine protease inhibitor serpinE2 is overexpressed in breast cancer and has been shown to foster metastatic spread. Here, we investigated the hypothesis that serpinE2 creates tumor-promoting conditions in the tumor microenvironment (TME) by affecting extracellular matrix remodeling. Using two different breast cancer models, we show that blocking serpinE2, either by knock-down (KD) in tumor cells or in response to a serpinE2 binding antibody, decreases metastatic dissemination from primary tumors to the lungs. We demonstrate that in response to serpinE2 KD or antibody treatment there are dramatic changes in the TME. Multiphoton intravital imaging revealed deposition of a dense extracellular collagen I matrix encapsulating serpinE2 KD or antibody-treated tumors. This is accompanied by a reduction in the population of tumor-promoting macrophages, as well as a decrease in chemokine ligand 2, which is known to affect macrophage abundance and polarization. In addition, TIMP-1 secretion is increased, which may directly inhibit matrix metalloproteases critical for collagen degradation in the tumor. In summary, our findings suggest that serpinE2 is required in the extracellular milieu of tumors where it acts in multiple ways to regulate tumor matrix deposition, thereby controlling tumor cell dissemination. PMID:27793045

  18. Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

    DTIC Science & Technology

    2014-09-01

    tissues and compare the expression levels in normal mouse mammary gland . For this, we used biological triplicates by preparing RNA from tumor tissues...homocysteine to be increased 4.5-fold in MMTV-HRAS mouse breast tumor tissues compared to age-matched wild type mouse mammary tissues. Similarly, the...levels of homocysteine went up 7.3-fold in MMTV-PyMT mouse breast cancer tissues 3 compared to age-matched wild type mouse mammary tissues

  19. High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity.

    PubMed

    Campesato, Luis Felipe; Silva, Ana Paula M; Cordeiro, Luna; Correa, Bruna R; Navarro, Fabio C P; Zanin, Rafael F; Marçola, Marina; Inoue, Lilian T; Duarte, Mariana L; Molgora, Martina; Pasqualini, Fabio; Massara, Matteo; Galante, Pedro; Barroso-Sousa, Romualdo; Polentarutti, Nadia; Riva, Federica; Costa, Erico T; Mantovani, Alberto; Garlanda, Cecilia; Camargo, Anamaria A

    2017-07-25

    Tumors develop numerous strategies to fine-tune inflammation and avoid detection and eradication by the immune system. The identification of mechanisms leading to local immune dysregulation is critical to improve cancer therapy. We here demonstrate that Interleukin-1 receptor 8 (IL-1R8 - previously known as SIGIRR/TIR8), a negative regulator of Toll-Like and Interleukin-1 Receptor family signaling, is up-regulated during breast epithelial cell transformation and in primary breast tumors. IL-1R8 expression in transformed breast epithelial cells reduced IL-1-dependent NF-κB activation and production of pro-inflammatory cytokines, inhibited NK cell activation and favored M2-like macrophage polarization. In a murine breast cancer model (MMTV-neu), IL-1R8-deficiency reduced tumor growth and metastasis and was associated with increased mobilization and activation of immune cells, such as NK cells and CD8+ T cells. Finally, immune-gene signature analysis in clinical specimens revealed that high IL-1R8 expression is associated with impaired innate immune sensing and T-cell exclusion from the tumor microenvironment. Our results indicate that high IL-1R8 expression acts as a novel immunomodulatory mechanism leading to dysregulated immunity with important implications for breast cancer immunotherapy.

  20. 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.

  1. Three-dimensional breast cancer models mimic hallmarks of size-induced tumor progression

    PubMed Central

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

    2016-01-01

    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. PMID:27216179

  2. Quantitative Study of Thermal Disturbances Due to Nonuniformly Perfused Tumors in Peripheral Regions of Women's Breast.

    PubMed

    Makrariya, Akshara; Adlakha, Neeru

    2017-01-01

    Mathematical modeling of biothermal processes is widely used to enhance the quantitative understanding of thermoregulation system of human body organs. This quantitative knowledge of thermal information of various human body organs can be used for developing clinical applications. In the past, investigators have studied thermal distribution in hemisphere-shaped human breast in the presence of sphere-shaped tumor. The shape and size of the breast as well as tumor may also affect thermal distribution which can have serious implications in thermography. In this article, a model of thermal disturbances in peripheral regions of ellipsoid-shaped human breast involving ellipse-shaped nonuniformly perfused tumor has been developed for a 2-dimensional steady-state case. The modeling study will provide biomedical scientists vital insights of thermal changes occurring due to the shape and size of breast and tumor which can influence the development of protocols of thermography for diagnosis of tumors in women's breast. We have incorporated the significant parameters such as blood flow, metabolic activity, and thermal conductivity in the thermal model for normal and malignant tissues. The controlled metabolic activity has been incorporated for normal tissues, and uncontrolled metabolic activity has been incorporated for tumor regions. The peripheral regions of breast are divided into 3 major layers, namely, epidermis, dermis, and subdermal tissues. An ellipse-shaped nonuniformly perfused tumor is assumed to be present in dermal layers. The nonuniformly perfused tumor is divided into 2 natural components, namely, the necrotic core and tumor periphery. The outer surface of the breast is assumed to be exposed to the environment, and the heat loss takes place by conduction, convection, radiation, and evaporation. The finite element approach is used to obtain the solution. The numerical results have been used to study the effect of shape and size of tumor on temperature

  3. Adipose tissue fatty acid composition in Greek patients with breast cancer versus those with benign breast tumors.

    PubMed

    De Bree, Eelco; Mamalakis, George; Sanidas, Elias; Hatzis, Christos; Askoxylakis, Ioannis; Daskalakis, Markos; Charalampakis, Vasileios; Tsibinos, George; Tsiftsis, Dimitris D; Kafatos, Anthony

    2013-04-01

    Fatty acid composition of adipose tissue is a most reliable biomarker of long-term dietary fatty acid intake. Few studies have implemented biomarkers of fatty acid intake in relation to breast cancer. In this study the relation between adipose tissue composition and breast cancer was investigated. Fatty acid composition in breast and buttock adipose tissue from 94 Greek women with breast cancer and 57 with benign breast tumors was determined. Multivariate analysis was performed to determine the association between fatty acid groups and breast cancer risk. In pre-menopausal women, elevated total polyunsaturated fatty acids (PUFA) in breast adipose tissue and N-3 PUFA in buttock adipose tissue were associated with reduced odds of breast cancer (odds ratio, OR=0.19; 95% confidence interval, CI=0.05-0.76, p<0.02 and OR=0.02; 95% CI=0.0009-0.36, p<0.009). Adipose total PUFA and N-3 PUFA were inversely-related to breast cancer risk in Greek pre-menopausal women. These results may have specific impact on habitual fat intake recommendations.

  4. Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer?

    PubMed Central

    Tabarestani, Sanaz; Motallebi, Marzieh; Akbari, Mohammad Esmaeil

    2016-01-01

    Context Breast cancer is the most common cancer in women worldwide. Estrogen receptor (ER) positive breast cancer constitutes the majority of these cancers. Hormone therapy has significantly improved clinical outcomes for early- and late-stage hormone receptor positive breast cancer. Although most patients with early stage breast cancer are treated with curative intent, approximately 20% - 30% of patients eventually experience a recurrence. During the last two decades, there have been tremendous efforts to understand the biological mechanisms of hormone therapy resistance, with the ultimate goal of implementing new therapeutic strategies to improve the current treatments for ER positive breast cancer. Several mechanisms of hormone therapy resistance have been proposed, including genetic alterations that lead to altered ER expression or ERs with changed protein sequence. Evidence Acquisition A Pubmed search was performed utilizing various related terms. Articles over the past 20 years were analyzed and selected for review. Results On the basis of published studies, the frequencies of ESR1 (the gene encoding ER) mutations in ER positive metastatic breast cancer range from 11% to 55%. Future larger prospective studies with standardized mutation detection methods may be necessary to determine the true incidence of ESR1 mutations. ESR1 amplification in breast cancer remains a controversial issue, with numerous studies either confirmed or challenged the reports of ESR1 amplification. The combination of intra-tumor heterogeneity regarding ESR1 copy number alterations and low level ESR1 copy number increase may account for these discrepancies. Conclusions While numerous unknown issues on the role of ESR1 mutations in advanced breast cancer remain, these new findings will certainly deepen current knowledge on molecular evolution of breast cancer and acquired resistance to hormone therapy. PMID:27761212

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

    SciTech Connect

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

    2015-09-15

    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 (C{sub T}) 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 C{sub T} 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 C{sub T} were conducted. The results showed that C{sub T} was able to replace the other four image features for the classification task. Conclusions: The normalized

  6. Breast-feeding and Wilms tumor: a report from the Children's Oncology Group.

    PubMed

    Saddlemire, Stephanie; Olshan, Andrew F; Daniels, Julie L; Breslow, Norman E; Bunin, Greta R; Ross, Julie A

    2006-06-01

    Previous research has shown that breast-feeding offers many nutritional benefits to children including protection against infection and possibly a decreased risk of childhood cancer. We investigated the association between breast-feeding and Wilms tumor, a childhood kidney tumor. We used data from a large case-control study in the United States and Canada. Cases were children under age 16 years who were diagnosed with Wilms tumor from 1999 to 2002 and were participating in the National Wilms Tumor Study. Controls were identified by random-digit dialing and were age and region matched to cases. Mothers of 501 cases and 480 controls provided information on breast-feeding by telephone interviews. Breast-feeding was associated with a reduced risk of Wilms tumor [adjusted odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.5-0.9]. Longer duration did not provide any additional reduction in risk. When stratified by maternal education, breast-feeding lowered risk among children whose mothers had less than a college education (OR = 0.6; 95% CI = 0.4-0.8) but not for mothers who had a college degree or more (OR = 1.1; 95% CI = 0.6-1.9). The results of this study are suggestive of an association between breast-feeding and Wilms tumor, but further research is needed to confirm this relationship.

  7. Aberrant CBFA2T3B gene promoter methylation in breast tumors

    PubMed Central

    Bais, Anthony J; Gardner, Alison E; McKenzie, Olivia LD; Callen, David F; Sutherland, Grant R; Kremmidiotis, Gabriel

    2004-01-01

    Background The CBFA2T3 locus located on the human chromosome region 16q24.3 is frequently deleted in breast tumors. CBFA2T3 gene expression levels are aberrant in breast tumor cell lines and the CBFA2T3B isoform is a potential tumor suppressor gene. In the absence of identified mutations to further support a role for this gene in tumorigenesis, we explored whether the CBFA2T3B promoter region is aberrantly methylated and whether this correlates with expression. Results Aberrant hypo and hypermethylation of the CBFA2T3B promoter was detected in breast tumor cell lines and primary breast tumor samples relative to methylation index interquartile ranges in normal breast counterpart and normal whole blood samples. A statistically significant inverse correlation between aberrant CBFA2T3B promoter methylation and gene expression was established. Conclusion CBFA2T3B is a potential breast tumor suppressor gene affected by aberrant promoter methylation and gene expression. The methylation levels were quantitated using a second-round real-time methylation-specific PCR assay. The detection of both hypo and hypermethylation is a technicality regarding the methylation methodology. PMID:15301688

  8. Progressive APOBEC3B mRNA expression in distant breast cancer metastases

    PubMed Central

    Dalm, Simone U.; de Weerd, Vanja; Moelans, Cathy B.; ter Hoeve, Natalie; van Diest, Paul J.; Martens, John W. M.; van Deurzen, Carolien H. M.

    2017-01-01

    Background APOBEC3B was recently identified as a gain-of-function enzymatic source of mutagenesis, which may offer novel therapeutic options with molecules that specifically target this enzyme. In primary breast cancer, APOBEC3B mRNA is deregulated in a substantial proportion of cases and its expression is associated with poor prognosis. However, its expression in breast cancer metastases, which are the main causes of breast cancer-related death, remained to be elucidated. Patients and methods RNA was isolated from 55 primary breast cancers and paired metastases, including regional lymph node (N = 20) and distant metastases (N = 35). APOBEC3B mRNA levels were measured by RT-qPCR. Expression levels of the primary tumors and corresponding metastases were compared, including subgroup analysis by estrogen receptor (ER/ESR1) status. Results Overall, APOBEC3B mRNA levels of distant metastases were significantly higher as compared to the corresponding primary breast tumor (P = 0.0015), an effect that was not seen for loco-regional lymph node metastases (P = 0.23). Subgroup analysis by ER-status showed that increased APOBEC3B levels in distant metastases were restricted to metastases arising from ER-positive primary breast cancers (P = 0.002). However, regarding ER-negative primary tumors, only loco-regional lymph node metastases showed increased APOBEC3B expression when compared to the corresponding primary tumor (P = 0.028). Conclusion APOBEC3B mRNA levels are significantly higher in breast cancer metastases as compared to the corresponding ER-positive primary tumors. This suggests a potential role for APOBEC3B in luminal breast cancer progression, and consequently, a promising role for anti-APOBEC3B therapies in advanced stages of this frequent form of breast cancer. PMID:28141868

  9. Superior anti-tumor efficacy of diisopropylamine dichloroacetate compared with dichloroacetate in a subcutaneous transplantation breast tumor model

    PubMed Central

    Yan, Chen; Chen, Aiping; Meng, Gang; Wei, Jiwu; Yu, Decai; Ding, Yitao

    2016-01-01

    Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, has anti-tumor properties in various carcinoma models. Diisopropylamine dichloroacetate (DADA), an over-the-counter drug for chronic liver disease, is a derivative of DCA. To date, few studies have evaluated the anticancer potential of DADA in breast cancer. In this study, MDA-MB-231 cells, a breast adenocarcinoma cell line, were used in in vitro and in vivo experiments to evaluate the anti-tumor efficacy of DADA and DCA. The half maximal inhibitory concentration (IC50) of DADA (7.1 ± 1.1 mmol/L) against MDA-MB-231 cells was significantly lower than that of DCA (15.6 ± 2.0 mmol/L); 100 mg/kg (0.0004 mol/kg) DADA was better than 100 mg/kg (0.0008 mol/kg) DCA at suppressing the growth of subcutaneous transplantation breast tumor at the same dose after 24 days intervention. Histological examination showed that both DCA and DADA interventions led to necrosis, inflammation, and fibrosis of tumor tissue in a mouse subcutaneous transplantation breast tumor model. DADA treatment inhibited Ki67 expression in tumor tissue. In vitro experiments showed that DADA could inhibit lactic acid production and glucose uptake in MDA-MB-231 cells at 10 mmol/L and these effects were stronger than DCA. DADA administration also induced complete autophagy during early treatment stages and incomplete autophagy and cell death at later treatment stages. In conclusion, DADA showed better anti-tumor efficacy than DCA in a breast cancer model. PMID:27582548

  10. Malignant phyllodes tumor of the breast with liposarcomatous differentiation and intraductal hyperplasia.

    PubMed

    Ayadi-Kaddour, Aïda; Zeddini, Abdelfatteh; Braham, Emna; Ismail, Olfa; Mlika, Mona; Guelmami, Karim; El Mezni, Faouzi

    2015-01-01

    Phyllodes tumor of the breast is a biphasic fibroepithelial neoplasm. 10 to 20% of phyllodes tumor show malignant transformation, often in the form of stroma, which usually shows fibrosarcomatous differentiation and rarely heterologous sarcomatous elements. Liposarcomatous differentiation is not common among phyllodes tumors. The correct diagnosis of heterologous liposarcomatous differentiation in a malignant PT requires identification of the biphasic component of the tumor. We reported a case of malignant phyllodes tumor which initially transformed into liposarcoma, in addition to a very rare intraductal hyperplasia and flat epithelial atypia. The patient was a 75-year-old woman, with a lump in the left breast without axillary lymphadenopathy. She also have a positive family history of breast carcinoma. She underwent surgery and still alive and disease free after one year.

  11. 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.

  12. Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications.

    PubMed

    Kimbung, Siker; Kovács, Anikó; Danielsson, Anna; Bendahl, Pär-Ola; Lövgren, Kristina; Frostvik Stolt, Marianne; Tobin, Nicholas P; Lindström, Linda; Bergh, Jonas; Einbeigi, Zakaria; Fernö, Mårten; Hatschek, Thomas; Hedenfalk, Ingrid

    2015-10-20

    The relevance of the intrinsic subtypes for clinical management of metastatic breast cancer is not comprehensively established. We aimed to evaluate the prevalence and prognostic significance of drifts in tumor molecular subtypes during breast cancer progression. A well-annotated cohort of 304 women with advanced breast cancer was studied. Tissue microarrays of primary tumors and synchronous lymph node metastases were constructed. Conventional biomarkers were centrally assessed and molecular subtypes were assigned following the 2013 St Gallen guidelines. Fine-needle aspirates of asynchronous metastases were transcriptionally profiled and subtyped using PAM50. Discordant expression of individual biomarkers and molecular subtypes was observed during tumor progression. Primary luminal-like tumors were relatively unstable, frequently adopting a more aggressive subtype in the metastases. Notably, loss of ER expression and a luminal to non-luminal subtype conversion was associated with an inferior post-recurrence survival. In addition, ER and molecular subtype assessed at all tumor progression stages were independent prognostic factors for post-recurrence breast cancer mortality in multivariable analyses. Our results demonstrate that drifts in tumor molecular subtypes may occur during tumor progression, conferring adverse consequences on outcome following breast cancer relapse.

  13. Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications

    PubMed Central

    Kimbung, Siker; Kovács, Anikó; Danielsson, Anna; Bendahl, Pär-Ola; Lövgren, Kristina; Stolt, Marianne Frostvik; Tobin, Nicholas P.; Lindström, Linda; Bergh, Jonas; Einbeigi, Zakaria; Fernö, Mårten; Hatschek, Thomas; Hedenfalk, Ingrid

    2015-01-01

    The relevance of the intrinsic subtypes for clinical management of metastatic breast cancer is not comprehensively established. We aimed to evaluate the prevalence and prognostic significance of drifts in tumor molecular subtypes during breast cancer progression. A well-annotated cohort of 304 women with advanced breast cancer was studied. Tissue microarrays of primary tumors and synchronous lymph node metastases were constructed. Conventional biomarkers were centrally assessed and molecular subtypes were assigned following the 2013 St Gallen guidelines. Fine-needle aspirates of asynchronous metastases were transcriptionally profiled and subtyped using PAM50. Discordant expression of individual biomarkers and molecular subtypes was observed during tumor progression. Primary luminal-like tumors were relatively unstable, frequently adopting a more aggressive subtype in the metastases. Notably, loss of ER expression and a luminal to non-luminal subtype conversion was associated with an inferior post-recurrence survival. In addition, ER and molecular subtype assessed at all tumor progression stages were independent prognostic factors for post-recurrence breast cancer mortality in multivariable analyses. Our results demonstrate that drifts in tumor molecular subtypes may occur during tumor progression, conferring adverse consequences on outcome following breast cancer relapse. PMID:26375671

  14. Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.

    PubMed

    Jameera Begam, A; Jubie, S; Nanjan, M J

    2017-04-01

    Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described.

  15. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2015-01-01

    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.

  17. New approach to breast tumor detection based on fluorescence x-ray analysis

    PubMed Central

    Hayashi, Yasuhiko; Okuyama, Fumio

    2010-01-01

    A new technical approach to breast-tumor detection is proposed. The technique is based on fluorescence x-ray analysis, and can identify a miniature malignant tumor within the breast. The primary beam intensity needed in fluorescence x-ray analysis is on a lower order of magnitude than that used in mammography. Thus, the newly-proposed technique would enable detection of a still tiny breast cancer while dramatically lowering the radiation dose. Field-emission x-ray sources might be a key for translating this concept into a medical technique. PMID:20930932

  18. Coexistence of benign phyllodes tumor and invasive ductal carcinoma in distinct breasts: case report.

    PubMed

    Neto, Guerino Barbalaco; Rossetti, Claudia; Souza, Natalia A; LA Fonseca, Fernando; Azzalis, Ligia Ajaime; Junqueira, Virginia Berlanga Campos; Valenti, Vitor E; de Abreu, Luiz Carlos

    2012-04-25

    This report describes a rare case of coexistence of benign phyllodes tumor, which measured 9 cm in the right breast, and invasive ductal carcinoma of 6 cm in the left breast, synchronous and independent, in a 66-year-old patient. The patient underwent a bilateral mastectomy due to the size of both lesions. Such situations are rare and usually refer to the occurrence of ductal or lobular carcinoma in situ when associated with malignant phyllodes tumors, and more often in ipsilateral breast or intra-lesional.

  19. Coexistence of benign phyllodes tumor and invasive ductal carcinoma in distinct breasts: case report

    PubMed Central

    2012-01-01

    This report describes a rare case of coexistence of benign phyllodes tumor, which measured 9 cm in the right breast, and invasive ductal carcinoma of 6 cm in the left breast, synchronous and independent, in a 66-year-old patient. The patient underwent a bilateral mastectomy due to the size of both lesions. Such situations are rare and usually refer to the occurrence of ductal or lobular carcinoma in situ when associated with malignant phyllodes tumors, and more often in ipsilateral breast or intra-lesional. PMID:22534285

  20. Estrogen receptor α regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function

    PubMed Central

    Felzen, V; Hiebel, C; Koziollek-Drechsler, I; Reißig, S; Wolfrum, U; Kögel, D; Brandts, C; Behl, C; Morawe, T

    2015-01-01

    Breast cancer is a heterogeneous disease and approximately 70% of newly diagnosed breast cancers are estrogen receptor (ER) positive. Out of the two ER types, α and β, ERα is the only ER that is detectable by immunohistochemistry in breast cancer biopsies and is the predominant subtype expressed in breast tumor tissue. ER-positive tumors are currently treated with anti-hormone therapy to inhibit ER signaling. It is well known that breast cancer cells can develop endocrine resistance and resistance to anti-hormone therapy and this can be facilitated via the autophagy pathway, but so far the description of a detailed autophagy expression profile of ER-positive cancer cells is missing. In the present study, we characterized tumor cell lines ectopically expressing ERα or ERβ as well as the breast cancer-derived MCF-7 cell line endogenously expressing ERα but being ERβ negative. We could show that ERα-expressing cells have a higher autophagic activity than cells expressing ERβ and cells lacking ER expression. Additionally, for autophagy-related gene expression we describe an ERα-specific ‘autophagy-footprint' that is fundamentally different to tumor cells expressing ERβ or lacking ER expression. This newly described ERα-mediated and estrogen response element (ERE)-independent non-canonical autophagy pathway, which involves the function of the co-chaperone Bcl2-associated athanogene 3 (BAG3), is independent of classical mammalian target of rapamycin (mTOR) and phosphatidylinositol 3 kinase (PI3K) signaling networks and provides stress resistance in our model systems. Altogether, our study uncovers a novel non-canonical autophagy pathway that might be an interesting target for personalized medicine and treatment of ERα-positive breast cancer cells that do not respond to anti-hormone therapy and classical autophagy inhibitors. PMID:26158518

  1. Breast tumor malignancy modelling using evolutionary neural logic networks.

    PubMed

    Tsakonas, Athanasios; Dounias, Georgios; Panagi, Georgia; Panourgias, Evangelia

    2006-01-01

    The present work proposes a computer assisted methodology for the effective modelling of the diagnostic decision for breast tumor malignancy. The suggested approach is based on innovative hybrid computational intelligence algorithms properly applied in related cytological data contained in past medical records. The experimental data used in this study were gathered in the early 1990s in the University of Wisconsin, based in post diagnostic cytological observations performed by expert medical staff. Data were properly encoded in a computer database and accordingly, various alternative modelling techniques were applied on them, in an attempt to form diagnostic models. Previous methods included standard optimisation techniques, as well as artificial intelligence approaches, in a way that a variety of related publications exists in modern literature on the subject. In this report, a hybrid computational intelligence approach is suggested, which effectively combines modern mathematical logic principles, neural computation and genetic programming in an effective manner. The approach proves promising either in terms of diagnostic accuracy and generalization capabilities, or in terms of comprehensibility and practical importance for the related medical staff.

  2. Targeting Unique Metabolic Properties of Breast Tumor Initiating Cells

    PubMed Central

    Feng, Weiguo; Gentles, Andrew; Nair, Ramesh V.; Huang, Min; Lin, Yuan; Lee, Cleo Y.; Cai, Shang; Scheeren, Ferenc A.; Kuo, Angera H.; Diehn, Maximilian

    2014-01-01

    Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about heterogeneity of metabolic properties cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to non-tumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs under-express genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, play a critical role in promoting the pro-glycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminates TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a promising strategy for targeting these cells. PMID:24497069

  3. HER2-Positive Circulating Tumor Cells in Breast Cancer

    PubMed Central

    Ignatiadis, Michail; Rothé, Françoise; Chaboteaux, Carole; Durbecq, Virginie; Rouas, Ghizlane; Criscitiello, Carmen; Metallo, Jessica; Kheddoumi, Naima; Singhal, Sandeep K.; Michiels, Stefan; Veys, Isabelle; Rossari, José; Larsimont, Denis; Carly, Birgit; Pestrin, Marta; Bessi, Silvia; Buxant, Frédéric; Liebens, Fabienne; Piccart, Martine; Sotiriou, Christos

    2011-01-01

    Purpose Circulating Tumor Cells (CTCs) detection and phenotyping are currently evaluated in Breast Cancer (BC). Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging. Methods Spiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch®. Results Based on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluoresence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI) 0–8.4%) whereas 4.1% (95%CI 1.4–11.4%) of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS) had 1 HER2-positive CTC/22.5 mL, 7.9%, (95%CI 4.1–14.9%) of 101 women with non metastatic (M0) BC had ≥1 HER2-positive CTC/22.5 mL (median 1 cell, range 1–3 cells) and 35.9% (95%CI 22.7–51.9%) of 39 patients with metastatic BC had ≥1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1–42 cells). In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03). Conclusion HER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies. PMID:21264346

  4. Molecular Breast Imaging: Use of a Dual-Head Dedicated Gamma Camera to Detect Small Breast Tumors

    PubMed Central

    Hruska, Carrie B.; Phillips, Stephen W.; Whaley, Dana H.; Rhodes, Deborah J.; O’Connor, Michael K.

    2014-01-01

    OBJECTIVE Molecular breast imaging with a single-head cadmium zinc telluride (CZT) gamma camera has previously been shown to have good sensitivity for the detection of small lesions. To further improve sensitivity, we developed a dual-head molecular breast imaging system using two CZT detectors to simultaneously acquire opposing breast views and reduce lesion-to-detector distance. We determined the incremental gain in sensitivity of molecular breast imaging with dual detectors. SUBJECTS AND METHODS Patients with BI-RADS category 4 or 5 lesions < 2 cm that were identified on mammography or sonography and scheduled for biopsy underwent molecular breast imaging as follows: After injection of 740 MBq of technetium-99m (99mTc) sestamibi, 10-minute craniocaudal and mediolateral oblique views of each breast were acquired. Blinded reviews were performed using images from both detectors 1 and 2 and images from detector 1 only (simulating a single-head system). Lesions were scored on a scale of 1–5; 2 or higher was considered positive. RESULTS Of the 150 patients in the study, 128 cancers were confirmed in 88 patients. Averaging the results from the three blinded readers, the sensitivity of dual-head molecular breast imaging was 90% (115/128), whereas the sensitivity from review of only single-head molecular breast imaging was 80% (102/128). The sensitivity for the detection of cancers ≤ 10 mm in diameter was 82% (50/61) for dual-head molecular breast imaging and 68% (41/61) for single-head molecular breast imaging. On average, 13 additional cancers were seen on dual-head images and the tumor uptake score increased by 1 or more in 60% of the identified tumors. CONCLUSION Gains in sensitivity with the dual-head system molecular breast imaging are partially due to increased confidence in lesion detection. Molecular breast imaging can reliably detect breast lesions < 2 cm and dual-head molecular breast imaging can significantly increase sensitivity for subcentimeter lesions

  5. Tracking nonpalpable breast cancer for breast-conserving surgery with carbon nanoparticles: implication in tumor location and lymph node dissection.

    PubMed

    Jiang, Yanyan; Lin, Nan; Huang, Sheng; Lin, Chongping; Jin, Na; Zhang, Zaizhong; Ke, Jun; Yu, Yinghao; Zhu, Jianping; Wang, Yu

    2015-03-01

    To examine the feasibility of using carbon nanoparticles to track nonpalpable breast cancer for breast-conserving surgery. During breast-conserving surgery, it is often very challenging to determine the boundary of tumor and identify involved lymph nodes. Currently used methods are useful in identifying tumor location, but do not provide direct visual guidance for resection margin during surgery. The study was approved by the Institutional Review Board of the Fuzhou General Hospital (Fuzhou, China). The current retrospective analysis included 16 patients with nonpalpable breast cancer receiving breast-conserving surgery under the guidance of preoperative marking using a carbon nanoparticle, as well as 3 patients receiving carbon nanoparticle marking followed by neoadjuvant treatment and then breast-conserving surgery. The Tumor Node Metastasis stage in the 16 cases included: T1N0M0 in 7, T1N1M0 in 2, T2N0M0 in 4, and T2N1M0 in the remaining 3 cases. The nanoparticle was injected at 12 sites at 0.5 cm away from the apparent edge under colored ultrasonography along 6 tracks separated by 60 degrees (2 sites every track). Lymph node status was also examined. The resection edge was free from cancer cells in all 16 cases (and the 3 cases with neoadjuvant treatment). Cancer cells were identified in majority of stained lymph nodes, but not in any of the unstained lymph nodes. No recurrence or metastasis was noticed after the surgery (2 to 22-month follow-up; median: 6 months). Tracking nonpalpable breast cancer with carbon nanoparticle could guide breast-conserving surgery.

  6. Predicting Sensitivity of Breast Tumors to Src-Targeted Therapies through Assessment of Cas/Src/BCAR3 Activity

    DTIC Science & Technology

    2016-10-01

    3-dimensional tissue culture models, transplantable mouse models of breast cancer , and analysis of human breast tumor samples. Major Findings: Key...results from the first year of support include (1) BCAR3 and Cas are co- expressed in multiple subtypes of breast cancer but not in normal mammary...regulator of tumor initiation in a transplantable murine model of breast cancer ; and (4) BCAR3 is essential for the ability of mammary epithelial cells to

  7. Fulvestrant, a selective estrogen receptor down-regulator, sensitizes estrogen receptor negative breast tumors to chemotherapy.

    PubMed

    Jiang, Donghai; Huang, Yuan; Han, Ning; Xu, Mingjie; Xu, Liang; Zhou, Lin; Wang, Shu; Fan, Weimin

    2014-05-01

    Drug resistance frequently results in poor prognosis and high 5-year recurrence rate in estrogen receptor-negative (ER-) breast cancer patients. Herein, we examined the reversal effects of fulvestrant on multidrug resistance (MDR) in ER- breast cancer cells. Co-administration of fulvestrant significantly sensitized ER- MDR tumors to paclitaxel both in vitro and in vivo. Further analyses indicated that fulvestrant did not affect P-gp expression, but could inhibit P-gp function and subsequently reverse P-gp mediated drug resistance in ER- breast cancer cells. These results showed that combination of fulvestrant and chemotherapeutic agents might provide an effective treatment for ER- MDR breast cancers.

  8. Breast metastases from an adrenocorticotropic hormone secreting thymic neuro-endocrine tumor.

    PubMed

    Gaur, Sumit; Ayyappan, Anoop P; Nahleh, Zeina

    2013-01-01

    Metastases to the breast from non-mammary sites are rare and pose a diagnostic and therapeutic challenge. They can be mistaken for primary breast malignancy, which is much more common. In this case report we describe the clinical, radiological and pathological features of a patient who developed breast metastases from an adrenocorticotropic hormone (ACTH) secreting thymic neuro-endocrine carcinoma. Patient was initially felt to have a primary breast malignancy, however, after further ancillary testing a diagnosis of metastatic thymic neuro-endocrine tumor was made.

  9. Interleukin-6 and pro inflammatory status in the breast tumor microenvironment.

    PubMed

    Sanguinetti, Alessandro; Santini, Donatella; Bonafè, Massimiliano; Taffurelli, Mario; Avenia, Nicola

    2015-03-28

    Greater than 50,000 new cases of breast cancer cases were diagnosed in Italy during 2013, with nearly 15,000 women succumbing to the disease. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer. The current review will focus on the impact of IL-6 and in the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchyme (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant. High serum levels of interleukin-6 correlate with poor outcome in breast cancer patients. However, few data are yet available on the relationship between IL-6 and stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Mammospheres (MS) from node invasive breast carcinoma tissues express IL-6 mRNA at higher levels than MS from matched non-neoplastic mammary glands. IL-6 mRNA is detectable only in basal-like breast carcinoma tissues; our results reveal that IL-6 triggers a Notch-3-dependent upregulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of MS and Michigan Cancer Foundation-7 (MCF-7)-derived spheroids. IL-6 induces a Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promotes a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. In conclusion, our data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing

  10. 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.

  11. Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer.

    PubMed

    Zhu, Menghai; Liu, Changzhen; Li, Shifei; Zhang, Shudong; Yao, Qi; Song, Qingkun

    2017-09-12

    Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Many patients suffer from bone metastasis. Sclerostin, a key regulator of normal bone remodeling, is critically involved in osteolytic bone diseases. However, its role in breast cancer bone metastasis remains unknown. Here, we found that sclerostin was overexpressed in breast cancer tumor tissues and cell lines. Inhibition of sclerostin by antibody (Scl-Ab) significantly reduced migration and invasion of MDA-MB-231 and MCF-7 cells in a time- and dose-dependent manner. In xenograft model, sclerostin inhibition improved survival of nude mice and prevented osteolytic lesions resulting from tumor metastasis. Taken together, sclerostin promotes breast cancer cell migration, invasion and bone osteolysis. Inhibition of sclerostin may serve as an efficient strategy for interventions against breast cancer bone metastasis or osteolytic bone diseases.

  12. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

    PubMed Central

    van Roosmalen, Wies; Le Dévédec, Sylvia E.; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; van de Water, Bob

    2015-01-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

  13. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

    PubMed

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

    2015-04-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

  14. Resistance to Targeted Therapies in Breast Cancer.

    PubMed

    Braga, Sofia

    2016-01-01

    Seventy five percent of all breast cancer (BC) patients express estrogen receptor (ER) but a quarter to half of patients with ER positive BC relapse on ET (endocrine therapy), tamoxifen, aromatase inhibitors (AIs), surgical castration, amongst other treatment strategies. ER positive BC at relapse loses ER expression in 20 % of cases and reduces quantitative ER expression most of the time. ER is not the only survival pathway driving ER positive BC and escape pathways intrinsic or acquired are activated during ET. This overview gives an account of ligand-independent ER activation, namely by receptor networks cross talk, and by the various genomic factors and mechanisms leading to ET response failure. Also the mechanisms of Her1 and Her2 inhibition resistance are dealt within this overview, along with the therapeutic indications and limitations of tyrosine kinase inhibitors, PARP inhibitors, PI3K/AKT/mTOR inhibitors, RAS/RAF/MEK/ERK/MAPK inhibitors, and antiangiogenic drugs. In spite of the many advances in controlling the division of BC cells and the progression of BC tumors these still remain the main cause of death among women in age range of 20-50 years requiring even more efforts in new therapeutic approaches besides the drugs within the scope of the overview.

  15. Juvenile fibroadenoma and granular cell tumor of the breast in an adolescent.

    PubMed

    Marshall, Andre P; Spottswood, Stephanie E; Grau, Ana M; Jackson, Gretchen Purcell

    2012-10-01

    We describe a case of a 15-year-old girl who presented with 2 painful masses in her right breast. Ultrasound confirmed the presence of 2 lesions, both of which appeared noncharacteristic for fibroadenomas. Both lesions were surgically resected. One was found to be a fibroadenoma and the other a granular cell tumor, both benign upon further histologic evaluation. Breast masses are rare in the pediatric population. The finding of a concurrent fibroadenoma and granular cell tumor is unique and has not been previously reported. Granular cell tumors of the breast are relatively uncommon. Often, they are mistaken for a breast malignancy. The concerning clinical and radiographic findings in this patient warranted operative excision.

  16. c-Kit expression and mutations in phyllodes tumors of the breast.

    PubMed

    Bose, Prithviraj; Dunn, S Terence; Yang, Jian; Allen, Richard; El-Khoury, Christian; Tfayli, Arafat

    2010-11-01

    Phyllodes tumors (PTs) represent uncommon fibroepithelial lesions of the breast that express c-Kit and platelet-derived growth factor receptor-alpha, similar to gastrointestinal stromal tumors (GISTs). 'Activating' mutations in these genes underlie responsiveness of GISTs to imatinib. Standard treatment for breast PTs is wide local excision, with no role for targeted therapies. c-Kit (CD117) expression was investigated by immunohistochemistry in 17 cases of breast PTs. Fourteen of these cases were also subjected to KIT mutation analysis by dideoxynucleotide sequencing. Five out of 17 (29%) tumors showed weak stromal staining for CD117. No previously described 'activating' mutations were found in exons 9, 11, 13, or 17 of the KIT gene. A silent germline point mutation was found in exon 17 of one case. These data do not suggest a pathogenetic role for KIT in breast PTs. Inhibition of c-Kit signaling is unlikely to be helpful in this condition.

  17. Ultrasonic Nakagami imaging: a strategy to visualize the scatterer properties of benign and malignant breast tumors.

    PubMed

    Tsui, Po-Hsiang; Yeh, Chih-Kuang; Liao, Yin-Yin; Chang, Chien-Cheng; Kuo, Wen-Hung; Chang, King-Jen; Chen, Chiung-Nien

    2010-02-01

    Previous studies have demonstrated the usefulness of the Nakagami parameter in characterizing breast tumors by ultrasound. However, physicians or radiologists may need imaging tools in a clinical setting to visually identify the properties of breast tumors. This study proposed the ultrasonic Nakagami image to visualize the scatterer properties of breast tumors and then explored its clinical performance in classifying benign and malignant tumors. Raw data of ultrasonic backscattered signals were collected from 100 patients (50 benign and 50 malignant cases) using a commercial ultrasound scanner with a 7.5 MHz linear array transducer. The backscattered signals were used to form the B-scan and the Nakagami images of breast tumors. For each tumor, the average Nakagami parameter was calculated from the pixel values in the region-of-interest in the Nakagami image. The receiver operating characteristic (ROC) curve was used to evaluate the clinical performance of the Nakagami image. The results showed that the Nakagami image shadings in benign tumors were different from those in malignant cases. The average Nakagami parameters for benign and malignant tumors were 0.69 +/- 0.12 and 0.55 +/- 0.12, respectively. This means that the backscattered signals received from malignant tumors tend to be more pre-Rayleigh distributed than those from benign tumors, corresponding to a more complex scatterer arrangement or composition. The ROC analysis showed that the area under the ROC curve was 0.81 +/- 0.04 and the diagnostic accuracy was 82%, sensitivity was 92% and specificity was 72%. The results showed that the Nakagami image is useful to distinguishing between benign and malignant breast tumors. 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  18. Isolation of a Breast Cancer Tumor Suppressor Gene from Chromosome 3p

    DTIC Science & Technology

    1998-10-01

    Kasumi at the Japanese Foundation Cancer Institute in Tokyo who has provided matched tumor/normal DNA samples from breast tumors. These samples will be...human chromosome 3p2l-p22. Proc. Natl. Acad. Sci. U. S. A., 89: 10877-10881, 1992. 10. Sato, T., Akiyama, F., Sakamoto, G., Kasumi , F., and Nakamura

  19. Tumor Twitter: Cellular Communication in the Breast Cancer Stem Cell Niche

    PubMed Central

    Brooks, Michael D.; Wicha, Max S.

    2015-01-01

    Summary Communication between the diverse assortment of cells that constitute the tumor microenvironment plays an important role in tumor development. Using a p53 null mouse model, Zhang and colleagues describe a novel feedback loop involving breast cancer stem cells and their progeny mediated by Wnt2, CXCL12, and IL6. PMID:25941337

  20. Investigation of Metastatic Breast Tumor Heterogeneity and Progression Using Dual Optical/SPECT Imaging

    DTIC Science & Technology

    2007-05-01

    the whole body image the prominent light source is the heart as the polymer . Agent washout produces a strong signal in the bladder.is a vascular...breast cancer tumor grows in the mammary fat pad, a whole body image shows anatomic details as well as the tumor; a higher magnification image reveals

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

    PubMed

    Schwab, Luciana P; Peacock, Danielle L; Majumdar, Debeshi; Ingels, Jesse F; Jensen, Laura C; Smith, Keisha D; Cushing, Richard C; Seagroves, Tiffany N

    2012-01-07

    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. 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. 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. These results demonstrate

  2. 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

  3. 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

  4. 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

  5. Effects of Herceptin on circulating tumor cells in HER2 positive early breast cancer.

    PubMed

    Zhang, J-L; Yao, Q; Chen Y Wang, J-H; Wang, H; Fan, Q; Ling, R; Yi, J; Wang, L

    2015-03-20

    The objective of this study was to determine the changes in peripheral blood circulating tumor cells in HER2-positive early breast cancer before and after Herceptin therapy, and to explore the effects of the HER2 gene and Herceptin on circulating tumor cells. CK19 mRNA expression in peripheral blood was evaluated by qRT-PCR as an index of circulating tumor cells in 15 cases of HER-2-positive breast cancer and 18 cases of HER2-negative breast cancer before, and after chemotherapy as well. Ten cases of HER2-positive breast cancer continued on Herceptin therapy for 3 months after chemotherapy, and their peripheral blood was again drawn and assayed for CK-19 mRNA expression. Preoperatively, all cases of HER2-positive cancer were positive for CK19 mRNA in peripheral blood, but 6 cases of HER2-negative breast cancer were positive (33.3%), where there was a substantial difference between the two groups. After 6 cycles of adjuvant chemotherapy, CK19 positive rates in cases of HER2-positive and -negative breast cancer reduced by 93.3 and 11.1%, respectively, with a significant difference still existing. After 3 months of Herceptin therapy, expression of CK19 mRNA declined considerably in 10 cases of HER2 positive breast cancer (113.66 ± 88.65 vs 63.35 ± 49.27, P = 0.025). HER-2 gene expression closely correlated with circulating tumor cells in peripheral blood of early breast cancer patients. Moreover, Herceptin, a monoclonal antibody for HER2, can reduce the number of circulating tumor cells, which can be an early predictive factor for Herceptin therapy effectiveness against breast cancer.

  6. "Missed" diagnoses of phyllodes tumor on breast biopsy: pathologic clues to its recognition.

    PubMed

    Yohe, Sophia; Yeh, I-Tien

    2008-04-01

    Fibroadenoma and phyllodes tumors of the breast exhibit a continuum of pathologic features. We examined phyllodes tumors initially called fibroadenoma for features that may accurately classify the tumor as phyllodes tumor on the first biopsy specimen. The phyllodes tumors initially called fibroadenoma for features that may accurately classify the tumor as phyllodes tumors on the first biopsy specimen are examined. Fifteen patients with phyllodes tumors were studied, initially called FA or another term short of PT. These tumors were compared with 16 true fibroadenomas, all with needle-core biopsy followed by excision. Resected phyllodes tumors were larger on average than fibroadenoma, 6.8 cm (range = 1.7-16.2 cm) versus 2.6 cm (range = 1.0-4.8 cm). In needle-core biopsy cases, sampling was limited, even in large breast masses. p53 and cleaved caspase-3 were noncontributory. Ki-67 showed higher proliferation indices in phyllodes tumors versus fibroadenoma (4.8% vs 0.6%). Features suggesting phyllodes tumors include tissue fragmentation, increased stromal cellularity especially around glands, stromal overgrowth, and increased mitoses. Increased sampling of a large tumor will likely yield more correct diagnoses.

  7. Evaluation of PDE5 and PDE9 expression in benign and malignant breast tumors.

    PubMed

    Karami-Tehrani, Fatemeh; Moeinifard, Marzieh; Aghaei, Mahmoud; Atri, Morteza

    2012-08-01

    Phosphodiesterases 5 and 9 (PDE5, PDE9) are enzymes responsible for regulating second messenger signaling by hydrolyzing 3',5' cyclic guanosine monophospha