BCoR-L1 variation and breast cancer.

PubMed

Lose, Felicity; Arnold, Jeremy; Young, David B; Brown, Carolyn J; Mann, Graham J; Pupo, Gulietta M; Khanna, Kum Kum; Chenevix-Trench, Georgia; Spurdle, Amanda B

2007-01-01

BRCA1 is involved in numerous essential processes in the cell, and the effects of BRCA1 dysfunction in breast cancer carcinogenesis are well described. Many of the breast cancer susceptibility genes such as BRCA2, p53, ATM, CHEK2, and BRIP1 encode proteins that interact with BRCA1. BCL6 corepressor-like 1 (BCoR-L1) is a newly described BRCA1-interacting protein that displays high homology to several proteins known to be involved in the fundamental processes of DNA damage repair and transcription regulation. BCoR-L1 has been shown to play a role in transcription corepression, and expression of the X-linked BCoR-L1 gene has been reported to be dysregulated in breast cancer subjects. BCoR-L1 is located on the X chromosome and is subject to X inactivation. We performed mutation analysis of 38 BRCA1/2 mutation-negative breast cancer families with male breast cancer, prostate cancer, and/or haplotype sharing around BCoR-L1 to determine whether there is a role for BCoR-L1 as a high-risk breast cancer predisposition gene. In addition, we conducted quantitative real-time PCR (qRT-PCR) on lymphoblastoid cell lines (LCLs) from the index cases from these families and a number of cancer cell lines to assess the role of BCoR-L1 dysregulation in cancer and cancer families. Very little variation was detected in the coding region, and qRT-PCR analysis revealed that BCoR-L1 expression is highly variable in cancer-free subjects, high-risk breast cancer patients, and cancer cell lines. We also report the investigation of a new expression control, DIDO1 (death inducer-obliterator 1), that is superior to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and UBC (ubiquitin C) for analysis of expression in LCLs. Our results suggest that BCoR-L1 expression does not play a large role in predisposition to familial breast cancer.

Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population.

PubMed

Ahern, Thomas P; Sprague, Brian L; Bissell, Michael C S; Miglioretti, Diana L; Buist, Diana S M; Braithwaite, Dejana; Kerlikowske, Karla

2017-06-01

Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density. Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1 st -degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density. Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0-2.1 at age 40; RR, 1.5; 95% CI, 1.3-1.7 at age 50; RR, 1.4; 95% CI, 1.2-1.6 at age 60; RR, 1.3; 95% CI, 1.1-1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1-3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88-1.5 at age 70). Associations did not change substantially when adjusted for breast density. Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history. Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938-44. ©2017 AACR . ©2017 American Association for Cancer Research.

SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer

PubMed Central

Burgess, Joshua T.; Bolderson, Emma; Saunus, Jodi M.; Zhang, Shu-Dong; Reid, Lynne E.; McNicol, Anne Marie; Lakhani, Sunil R.; Cuff, Katharine; Richard, Kerry; Richard, Derek J.; O'Byrne, Kenneth J.

2016-01-01

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines. Subsequent in silico connectivity screening demonstrated that the clinically approved antihistamine drug, chloropyramine, increased SASH1 mRNA levels. Chloropyramine has previously been shown to have anti-tumour activity in breast cancer in part through modulation of FAK signalling, a pathway also regulated by SASH1. This study demonstrated that chloropyramine increased SASH1 protein levels in breast cancer cells. Consistent with this the agent reduced cell confluency in 7/8 cell lines treated irrespective of their ER status but not apoptosis incompetent MCF7 cells. In contrast SASH1 siRNA-transfected breast cancer cells exhibited reduced chloropyramine sensitivity. The prognostic significance of SASH1 expression was also investigated in two breast cancer cohorts. Expression was associated with favourable outcome in ER-positive cases, but only those of low histological grade/proliferative status. Conversely, we found a very strong inverse association in HER2+ disease irrespective of ER status, and in triple-negative, basal-like cases. Overall, the data suggest that SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. Pharmacologic induction of SASH1 by chloropyramine treatment of breast cancer warrants further preclinical and clinical investigation. PMID:27637080

SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.

PubMed

Burgess, Joshua T; Bolderson, Emma; Saunus, Jodi M; Zhang, Shu-Dong; Reid, Lynne E; McNicol, Anne Marie; Lakhani, Sunil R; Cuff, Katharine; Richard, Kerry; Richard, Derek J; O'Byrne, Kenneth J

2016-11-08

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines. Subsequent in silico connectivity screening demonstrated that the clinically approved antihistamine drug, chloropyramine, increased SASH1 mRNA levels. Chloropyramine has previously been shown to have anti-tumour activity in breast cancer in part through modulation of FAK signalling, a pathway also regulated by SASH1. This study demonstrated that chloropyramine increased SASH1 protein levels in breast cancer cells. Consistent with this the agent reduced cell confluency in 7/8 cell lines treated irrespective of their ER status but not apoptosis incompetent MCF7 cells. In contrast SASH1 siRNA-transfected breast cancer cells exhibited reduced chloropyramine sensitivity. The prognostic significance of SASH1 expression was also investigated in two breast cancer cohorts. Expression was associated with favourable outcome in ER-positive cases, but only those of low histological grade/proliferative status. Conversely, we found a very strong inverse association in HER2+ disease irrespective of ER status, and in triple-negative, basal-like cases. Overall, the data suggest that SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. Pharmacologic induction of SASH1 by chloropyramine treatment of breast cancer warrants further preclinical and clinical investigation.

Breast Cancer Biology and Ethnic Disparities in Breast Cancer Mortality in New Zealand: A Cohort Study

PubMed Central

Seneviratne, Sanjeewa; Lawrenson, Ross; Scott, Nina; Kim, Boa; Shirley, Rachel; Campbell, Ian

2015-01-01

Introduction Indigenous Māori women have a 60% higher breast cancer mortality rate compared with European women in New Zealand. We investigated differences in cancer biological characteristics and their impact on breast cancer mortality disparity between Māori and NZ European women. Materials and Methods Data on 2849 women with primary invasive breast cancers diagnosed between 1999 and 2012 were extracted from the Waikato Breast Cancer Register. Differences in distribution of cancer biological characteristics between Māori and NZ European women were explored adjusting for age and socioeconomic deprivation in logistic regression models. Impacts of socioeconomic deprivation, stage and cancer biological characteristics on breast cancer mortality disparity between Māori and NZ European women were explored in Cox regression models. Results Compared with NZ European women (n=2304), Māori women (n=429) had significantly higher rates of advanced and higher grade cancers. Māori women also had non-significantly higher rates of ER/PR negative and HER-2 positive breast cancers. Higher odds of advanced stage and higher grade remained significant for Māori after adjusting for age and deprivation. Māori women had almost a 100% higher age and deprivation adjusted breast cancer mortality hazard compared with NZ European women (HR=1.98, 1.55-2.54). Advanced stage and lower proportion of screen detected cancer in Māori explained a greater portion of the excess breast cancer mortality (HR reduction from 1.98 to 1.38), while the additional contribution through biological differences were minimal (HR reduction from 1.38 to 1.35). Conclusions More advanced cancer stage at diagnosis has the greatest impact while differences in biological characteristics appear to be a minor contributor for inequities in breast cancer mortality between Māori and NZ European women. Strategies aimed at reducing breast cancer mortality in Māori should focus on earlier diagnosis, which will likely

Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability

DTIC Science & Technology

2015-11-01

increased PhScN potency as a result of preventing endoproteolytic degradation. Finally, the in vivo lung extravasation and colonization data, as well as...successful colonization are late stages in breast cancer progression that are ultimately fatal. Hence, prevention of extravasation which leads to colony...Award Number: TITLE: “Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma

Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sruewing, J.P.; Brody, L.C.; Erdos, M.R.

Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals.more » Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations. 37 refs., 1 fig., 1 tab.« less

IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

PubMed

Patel, Alpa V; Cheng, Iona; Canzian, Federico; Le Marchand, Loïc; Thun, Michael J; Berg, Christine D; Buring, Julie; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Cox, David G; Dorronsoro, Miren; Dossus, Laure; Haiman, Christopher A; Hankinson, Susan E; Henderson, Brian E; Hoover, Robert; Hunter, David J; Kaaks, Rudolf; Kolonel, Laurence N; Kraft, Peter; Linseisen, Jakob; Lund, Eiliv; Manjer, Jonas; McCarty, Catherine; Peeters, Petra H M; Pike, Malcolm C; Pollak, Michael; Riboli, Elio; Stram, Daniel O; Tjonneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tumino, Rosario; Yeager, Meredith; Ziegler, Regina G; Feigelson, Heather Spencer

2008-07-02

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

Targeting ESR1-Mutant Breast Cancer

DTIC Science & Technology

2015-09-01

AWARD NUMBER: W81XWH-14-1-0359 TITLE: Targeting ESR1 -Mutant Breast Cancer PRINCIPAL INVESTIGATOR: Dr. Sarat Chandarlapaty CONTRACTING...31 Aug 2015 4. TITLE AND SUBTITLE Targeting ESR1 -Mutant Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0359 5c. PROGRAM ELEMENT...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The hypothesis of this proposal is that LBD mutations in ESR1 promote resistance to

Psychosocial Adjustment and Perceived Risk Among Adolescent Girls From Families With BRCA1/2 or Breast Cancer History

PubMed Central

Patrick-Miller, Linda; Schwartz, Lisa A.; Egleston, Brian L.; Henry-Moss, Dare; Domchek, Susan M.; Daly, Mary B.; Tuchman, Lisa; Moore, Cynthia; Rauch, Paula K.; Shorter, Rebecca; Karpink, Kelsey; Sands, Colleen Burke

2016-01-01

Purpose To evaluate the impact of breast cancer family history and maternal BRCA1/2 mutation on the psychosocial adjustment and perceived risk in girls age 11 to 19 years old. Materials and Methods Girls age 11 to 19 years old with one or more relatives with breast cancer or a familial BRCA1/2 mutation (breast cancer family history [BCFH] positive, n = 208; n = 69 with BRCA1/2-positive mother), peers (BCFH negative, n = 112), and their mothers completed assessments of psychosocial adjustment, breast cancer–specific distress, and perceived risk of breast cancer. Results General psychosocial adjustment did not differ significantly between BCFH-positive and BCFH-negative girls, either by self-report or mother report, except for higher self-esteem among BCFH-positive girls (P = .01). BCFH-positive girls had higher breast cancer–specific distress than BCFH-negative girls (P < .001), but girls from BRCA1/2-positive families did not differ from other BCFH-positive peers. BCFH-positive girls were more likely to report themselves at increased self-risk for breast cancer in adulthood than BCFH-negative peers (74% v 33%, respectively; P ≤ .001). Girls from BRCA1/2-positive families were more likely than other BCFH-positive and BCFH-negative peers to report themselves at increased risk (P < .001). In all groups, perceived risk of breast cancer was associated with older age. Higher breast cancer–specific distress among adolescent girls was associated with higher self-perceived risk of breast cancer and higher maternal breast cancer–specific distress. Conclusion Adolescent girls from BRCA1/2-positive and breast cancer families have higher self-esteem and do not have poorer psychosocial adjustment than peers. However, they do experience greater breast cancer–specific distress and perceived risk of breast cancer, particularly among older girls. Understanding the impact is important to optimize responses to growing up in families at familial and genetic risk for breast

Perceived Versus Objective Breast Cancer, Breast Cancer Risk in Diverse Women

PubMed Central

Fehniger, Julia; Livaudais-Toman, Jennifer; Karliner, Leah; Kerlikowske, Karla; Tice, Jeffrey A.; Quinn, Jessica; Ozanne, Elissa

2014-01-01

Abstract Background: Prior research suggests that women do not accurately estimate their risk for breast cancer. Estimating and informing women of their risk is essential for tailoring appropriate screening and risk reduction strategies. Methods: Data were collected for BreastCARE, a randomized controlled trial designed to evaluate a PC-tablet based intervention providing multiethnic women and their primary care physicians with tailored information about breast cancer risk. We included women ages 40–74 visiting general internal medicine primary care clinics at one academic practice and one safety net practice who spoke English, Spanish, or Cantonese, and had no personal history of breast cancer. We collected baseline information regarding risk perception and concern. Women were categorized as high risk (vs. average risk) if their family history met criteria for referral to genetic counseling or if they were in the top 5% of risk for their age based on the Gail or Breast Cancer Surveillance Consortium Model (BCSC) breast cancer risk model. Results: Of 1,261 participants, 25% (N=314) were classified as high risk. More average risk than high risk women had correct risk perception (72% vs. 18%); 25% of both average and high risk women reported being very concerned about breast cancer. Average risk women with correct risk perception were less likely to be concerned about breast cancer (odds ratio [OR]=0.3; 95% confidence interval [CI]=0.2–0.4) while high risk women with correct risk perception were more likely to be concerned about breast cancer (OR=5.1; 95%CI=2.7–9.6). Conclusions: Many women did not accurately perceive their risk for breast cancer. Women with accurate risk perception had an appropriate level of concern about breast cancer. Improved methods of assessing and informing women of their breast cancer risk could motivate high risk women to apply appropriate prevention strategies and allay unnecessary concern among average risk women. PMID:24372085

Knocking down cyclin D1b inhibits breast cancer cell growth and suppresses tumor development in a breast cancer model.

PubMed

Wei, Min; Zhu, Li; Li, Yafen; Chen, Weiguo; Han, Baosan; Wang, Zhiwei; He, Jianrong; Yao, Hongliang; Yang, Zhongyin; Zhang, Qing; Liu, Bingya; Gu, Qinlong; Zhu, Zhenggang; Shen, Kunwei

2011-08-01

Cyclin D1 is aberrantly expressed in many types of cancers, including breast cancer. High levels of cyclin D1b, the truncated isoform of cyclin D1, have been reported to be associated with a poor prognosis for breast cancer patients. In the present study, we used siRNA to target cyclin D1b overexpression and assessed its ability to suppress breast cancer growth in nude mice. Cyclin D1b siRNA effectively inhibited overexpression of cyclin D1b. Depletion of cyclin D1b promoted apoptosis of cyclin D1b-overexpressing cells and blocked their proliferation and transformation phenotypes. Notably, cyclin D1b overexpression is correlated with triple-negative basal-like breast cancers, which lack specific therapeutic targets. Administration of cyclin D1b siRNA inhibited breast tumor growth in nude mice and cyclin D1b siRNA synergistically enhanced the cell killing effects of doxorubicin in cell culture, with this combination significantly suppressing tumor growth in the mouse model. In conclusion, the results indicate that cyclin D1b, which is overexpressed in breast cancer, may serve as a novel and effective therapeutic target. More importantly, the present study clearly demonstrated a very promising therapeutic potential for cyclin D1b siRNA in the treatment of cyclin D1b-overexpressing breast cancers, including the very malignant triple-negative breast cancers. © 2011 Japanese Cancer Association.

Locoregional treatment and overall survival of men with T1a,b,cN0M0 breast cancer: A population-based study.

PubMed

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

2017-01-01

Male breast cancer (MaBC) is an understudied disease; information about locoregional treatment and outcomes in patients with early stage is unknown. We aimed to analyse patient characteristics, locoregional treatment and overall survival (OS) of T1a,b,cN0M0 male breast cancer. We evaluated men with T1a,b,cN0M0 breast cancer reported to Surveillance, Epidemiology, and End Results program from 1988 to 2012. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. We included 1263 patients. Median age was 66 years (range 27-103). Median follow-up was 62 months (range 1-294). OS at 5 and 10 years were 85.1% and 66.5%, respectively. Distribution according to tumour sub-stage was: T1a 6.5%, T1b 20.7% and T1c 72.8%. Mastectomy was performed in >74% of patients of each tumour size group and overall 44.1% had >5 lymph nodes examined (LNE). Univariate analysis showed that patients with T1c, no surgery and 0 LNE had worse prognosis. In multivariate analysis, older age (hazard ratio [HR] 11.09), grade 3/4 tumours (HR 1.7), no surgery (HR 3.3), 0 LNE (HR 5.1) and unmarried patients (HR 1.7) had significantly shorter OS. There were no differences in OS between breast conservation versus mastectomy and 1-5 LNE versus > 5 LNE. Men with early breast cancer have a favourable OS. However, older age, higher grade, no breast surgery, no LNE and unmarried status emerged as poor prognostic characteristics. Efforts to decrease the high rates of mastectomy and extensive LNE should be taken given similar OS observed with breast conservation and 1-5 LNE, respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

RAD51B in Familial Breast Cancer

PubMed Central

Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Dörk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Dunning, Alison M.; García-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; Benitez, Javier; González-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Brüning, Thomas; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Van Dyck, Laurien; Janssen, Hilde; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Hallberg, Emily; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Dumont, Martine; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Devilee, Peter; Seynaeve, Caroline; Hooning, Maartje J.; Collée, Margriet; Cox, Angela; Cross, Simon S.; Shah, Mitul; Luben, Robert N.; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Couch, Fergus J.; Yannoukakos, Drakoulis; Orr, Nick; Swerdlow, Anthony; Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per; Easton, Douglas F.; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli

2016-01-01

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. PMID:27149063

Tracking Nonpalpable Breast Cancer for Breast-conserving Surgery With Carbon Nanoparticles

PubMed Central

Jiang, Yanyan; Lin, Nan; Huang, Sheng; Lin, Chongping; Jin, Na; Zhang, Zaizhong; Ke, Jun; Yu, Yinghao; Zhu, Jianping; Wang, Yu

2015-01-01

Abstract 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. PMID:25761181

Pregnancy-related Characteristics and Breast Cancer Risk

PubMed Central

Brasky, Theodore M.; Li, Yanli; Jaworowicz, David J.; Potischman, Nancy; Ambrosone, Christine B.; Hutson, Alan D.; Nie, Jing; Shields, Peter G.; Trevisan, Maurizio; Rudra, Carole B.; Edge, Stephen B.; Freudenheim, Jo L.

2013-01-01

Breast tissues undergo extensive physiologic changes during pregnancy, which may affect breast carcinogenesis. Gestational hypertension, pre-eclampsia/eclampsia, gestational diabetes, pregnancy weight gain, and nausea and vomiting (N&V) during pregnancy may be indicative of altered hormonal and metabolic profiles and could impact breast cancer risk. Here, we examined associations between these characteristics of a woman’s pregnancy and her subsequent breast cancer risk. Participants were parous women that were recruited to a population-based case-control study (Western New York Exposures and Breast Cancer Study). Cases (n=960), aged 35-79 years, had incident, primary, histologically-confirmed breast cancer. Controls (n=1,852) were randomly selected from Motor Vehicle records (<65 years) or Medicare rolls (≥65 years). Women were queried on their lifetime pregnancy experiences. Multivariable-adjusted logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). N&V during pregnancy was inversely associated with breast cancer risk. Relative to those who never experienced N&V, ever experiencing N&V was associated with decreased risk (OR 0.69, 95% CI: 0.56-0.84) as were increased N&V severity (P-trend<0.001), longer duration (P-trend<0.01), and larger proportion of affected pregnancies (P-trend<0.0001) among women with ≥3 pregnancies. Associations were stronger for more recent pregnancies (<5y). Findings did not differ by menopausal status or breast cancer subtype including estrogen receptor and HER2 expression status. Other pregnancy characteristics examined were not associated with risk. We observed strong inverse associations between pregnancy N&V and breast cancer risk. Replication of these findings and exploration of underlying mechanisms could provide important insight into breast cancer etiology and prevention. PMID:23737027

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.

PubMed

Kuchenbaecker, Karoline B; Hopper, John L; Barnes, Daniel R; Phillips, Kelly-Anne; Mooij, Thea M; Roos-Blom, Marie-José; Jervis, Sarah; van Leeuwen, Flora E; Milne, Roger L; Andrieu, Nadine; Goldgar, David E; Terry, Mary Beth; Rookus, Matti A; Easton, Douglas F; Antoniou, Antonis C; McGuffog, Lesley; Evans, D Gareth; Barrowdale, Daniel; Frost, Debra; Adlard, Julian; Ong, Kai-Ren; Izatt, Louise; Tischkowitz, Marc; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Nogues, Catherine; Lasset, Christine; Stoppa-Lyonnet, Dominique; Fricker, Jean-Pierre; Faivre, Laurence; Berthet, Pascaline; Hooning, Maartje J; van der Kolk, Lizet E; Kets, Carolien M; Adank, Muriel A; John, Esther M; Chung, Wendy K; Andrulis, Irene L; Southey, Melissa; Daly, Mary B; Buys, Saundra S; Osorio, Ana; Engel, Christoph; Kast, Karin; Schmutzler, Rita K; Caldes, Trinidad; Jakubowska, Anna; Simard, Jacques; Friedlander, Michael L; McLachlan, Sue-Anne; Machackova, Eva; Foretova, Lenka; Tan, Yen Y; Singer, Christian F; Olah, Edith; Gerdes, Anne-Marie; Arver, Brita; Olsson, Håkan

2017-06-20

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44

BRCA1-linked marker in postmenopausal breast cancer families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Folsom, A.R.; Chen, P.L.; Sellers, T.A.

1994-09-01

A majority of breast and ovarian cancer families and half of the early-onset breast cancer families are linked to markers on 17q (BRCA1). While linkage has been demonstrated in families with premenopausal disease, few studies have tested these markers in families with postmenopausal breast cancer. In the Iowa Women`s Health Study, a population-based study of over 42,000 women, an association of waist-to-hip ratio (WHR) with the risk of postmenopausal breast cancer was found predominantly in women with a positive family history -- this interaction was associated with a 3.2-fold elevated risk. This effect was even more pronounced when the definitionmore » of family history included breast and ovarian cancer, known to be linked to 17q markers. We evaluated evidence for linkage with D17S579, a BRCA-1-linked marker, in 13 families in which the index case had postmenopausal breast cancer. Genotyping for alleles at D17S579 was performed on 84 blood samples. Linkage analysis assumed that the breast cancer trait had an autosomal dominant mode of inheritance with a penetrance of 80%. For the 13 families studied, the maximum lod score was 0.29 at a theta of 0.27. There was significant evidence against tight linkage of breast cancer with D17S579 (theta<0.4). Heterogeneity analysis suggested evidence for the presence of both linked and unlinked families. Partitioning informative families on WHR of the index case suggested heterogeneity. These data suggest that, in a subset of families identified by a postmenopausal breast cancer proband, risk of breast cancer may be mediated by BRCA1, with heterogeneity defined by WHR.« less

Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of estrogen-receptor positive breast cancers

PubMed Central

Veeraraghavan, Jamunarani; Tan, Ying; Cao, Xi-Xi; Kim, Jin-Ah; Wang, Xian; Chamness, Gary C.; Maiti, Sourindra N.; Cooper, Laurence J. N.; Edwards, Dean P.; Contreras, Alejandro; Hilsenbeck, Susan G.; Chang, Eric C.; Schiff, Rachel; Wang, Xiao-Song

2014-01-01

Characterizing the genetic alterations leading to the more aggressive forms of estrogen receptor positive (ER+) breast cancers are of critical significance in breast cancer management. Here we identify recurrent rearrangements between estrogen receptor gene ESR1 and its neighbor CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal-B tumors, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170 positive tumors. These fusions encode N-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity, and enhanced xenograft tumor formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signaling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer. PMID:25099679

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

PubMed Central

Antoniou, Antonis C.; Spurdle, Amanda B.; Sinilnikova, Olga M.; Healey, Sue; Pooley, Karen A.; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Arnold, Norbert; Hofmann, Wera; Sutter, Christian; Niederacher, Dieter; Deissler, Helmut; Caldes, Trinidad; Kämpjärvi, Kati; Nevanlinna, Heli; Simard, Jacques; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Rebbeck, Timothy R.; Wagner, Theresa; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Ganz, Patricia A.; Daly, Mary B.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Blum, Joanne L.; Couch, Fergus J.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Szabo, Csilla I.; Pereira, Lutecia H. Mateus; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Barnett-Griness, Ofra; Andrulis, Irene L.; Ozcelik, Hilmi; Gerdes, Anne-Marie; Caligo, Maria A.; Laitman, Yael; Kaufman, Bella; Milgrom, Roni; Friedman, Eitan; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Llort, Gemma; Milne, Roger L.; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; Manders, Peggy; Ligtenberg, Marjolijn J.L.; van den Ouweland, Ans M.W.; Peock, Susan; Cook, Margaret; Platte, Radka; Evans, D. Gareth; Eeles, Rosalind; Pichert, Gabriella; Chu, Carol; Eccles, Diana; Davidson, Rosemarie; Douglas, Fiona; Godwin, Andrew K.; Barjhoux, Laure; Mazoyer, Sylvie; Sobol, Hagay; Bourdon, Violaine; Eisinger, François; Chompret, Agnès; Capoulade, Corinne; Bressac-de Paillerets, Brigitte; Lenoir, Gilbert M.; Gauthier-Villars, Marion; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.

2008-01-01

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20–1.45, ptrend = 1.7 × 10−8 and HR = 1.12, 95% CI: 1.02–1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06–1.20, ptrend = 5 × 10−5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers. PMID:18355772

Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis

PubMed Central

2011-01-01

Introduction Detection of serum biomarkers for early diagnosis of breast cancer remains an important goal. Changes in the structure of O-linked glycans occur in all breast cancers resulting in the expression of glycoproteins that are antigenically distinct. Indeed, the serum assay widely used for monitoring disease progression in breast cancer (CA15.3), detects a glycoprotein (MUC1), but elevated levels of the antigen cannot be detected in early stage patients. However, since the immune system acts to amplify the antigenic signal, antibodies can be detected in sera long before the antigen. We have exploited the change in O-glycosylation to measure autoantibody responses to cancer-associated glycoforms of MUC1 in sera from early stage breast cancer patients. Methods We used a microarray platform of 60mer MUC1 glycopeptides, to confirm the presence of autoantibodies to cancer associated glycoforms of MUC1 in a proportion of early breast cancer patients (54/198). Five positive sera were selected for detailed definition of the reactive epitopes using on chip glycosylation technology and a panel of glycopeptides based on a single MUC1 tandem repeat carrying specific glycans at specific sites. Based on these results, larger amounts of an extended repertoire of defined MUC1 glycopeptides were synthesised, printed on microarrays, and screened with sera from a large cohort of breast cancer patients (n = 395), patients with benign breast disease (n = 108) and healthy controls (n = 99). All sera were collected in the 1970s and 1980s and complete clinical follow-up of breast cancer patients is available. Results The presence and level of autoantibodies was significantly higher in the sera from cancer patients compared with the controls, and a highly significant correlation with age was observed. High levels of a subset of autoantibodies to the core3MUC1 (GlcNAcβ1-3GalNAc-MUC1) and STnMUC1 (NeuAcα2,6GalNAc-MUC1) glycoforms were significantly associated with reduced incidence

Persistent breast pain among women with histories of breast conserving surgery for breast cancer compared to women without histories of breast surgery or cancer

PubMed Central

Edmond, Sara N.; Shelby, Rebecca A.; Keefe, Francis J.; Fisher, Hannah M.; Schmidt, John; Soo, Mary Scott; Skinner, Celette Sugg; Ahrendt, Gretchen M.; Manculich, Jessica; Sumkin, Jules H.; Zuley, Margarita L.; Bovbjerg, Dana H.

2016-01-01

Objectives This study compared persistent breast pain among women who received breast-conserving surgery for breast cancer and women without a history of breast cancer. Methods Breast cancer survivors (n=200) were recruited at their first post-surgical surveillance mammogram (6-15 months post-surgery). Women without a breast cancer history (n=150) were recruited at the time of a routine screening mammogram. All women completed measures of breast pain, pain interference with daily activities and intimacy, worry about breast pain, anxiety symptoms, and depression symptoms. Demographic and medical information were also collected. Results Persistent breast pain (duration ≥ 6 months) was reported by 46.5% of breast cancer survivors and 12.7% of women without a breast cancer history (p<0.05). Breast cancer survivors also had significantly higher rates of clinically significant persistent breast pain (pain intensity score ≥3/10), as well as higher average breast pain intensity and unpleasantness scores. Breast cancer survivors with persistent breast pain had significantly higher levels of depressive symptoms, as well as pain worry and interference, compared to survivors without persistent breast pain or women without a breast cancer history. Anxiety symptoms were significantly higher in breast cancer survivors with persistent breast pain compared to women without a breast cancer history. Discussion Results indicate that persistent breast pain negatively impacts women with a history of breast conserving cancer surgery compared to women without that history. Strategies to ameliorate persistent breast pain and to improve adjustment among women with persistent breast pain should be explored for incorporation into standard care for breast cancer survivors. PMID:27922843

Cancer risk among Danish women with cosmetic breast implants.

PubMed

Friis, Søren; Hölmich, Lisbet R; McLaughlin, Joseph K; Kjøller, Kim; Fryzek, Jon P; Henriksen, Trine F; Olsen, Jørgen H

2006-02-15

The available epidemiologic evidence does not support a carcinogenic effect of silicone breast implants on breast or other cancers. Data on cancer risk other than breast cancer are limited and few studies have assessed cancer risk beyond 10-15 years after breast implantation. We extended follow-up of our earlier cohort study of Danish women with cosmetic breast implants by 7 years, yielding 30 years of follow-up for women with longest implant duration. The study population consisted of women who underwent cosmetic breast implant surgery at private clinics of plastic surgery (n = 1,653) or public hospitals (n = 1,110), and a control group of women who attended private clinics for other plastic surgery (n = 1,736), between 1973-95. Cancer incidence through 2002 was ascertained using the Danish Cancer Registry. Risk evaluation was based on computation of standardized incidence ratios (SIR) and Cox proportional hazards models, adjusting for age, calendar period and reproductive history. We observed 163 cancers among women with breast implants compared to 136.7 expected based on general population rates (SIR = 1.2; 95% confidence interval [CI] = 1.0-1.4), during a mean follow-up period of 14.4 years (range = 0-30 years). Women with breast implants experienced a reduced risk of breast cancer (SIR = 0.7; 95% CI = 0.5-1.0), and an increased risk of non-melanoma skin cancer (SIR = 2.1; 95% CI = 1.5-2.7). Stratification by age at implantation, calendar year at implantation and time since implantation showed no clear trends, however, the statistical precision was limited in these analyses. When excluding non-melanoma skin cancer, the SIR for cancer overall was 1.0 (95% CI = 0.8-1.2). With respect to other site-specific cancers, no significantly increased or decreased SIR were observed. Similar results were found when directly comparing women who had implants at private clinics with women who attended private clinics for other plastic surgery, with rate ratios for cancer

Mechanism of Twist1-Induced Invasion in Breast Cancer Metastasis

DTIC Science & Technology

2012-01-01

Breast Cancer Metastasis PRINCIPAL INVESTIGATOR: Mark Adam Eckert CONTRACTING...2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanism of Twist1-Induced Invasion in Breast Cancer Metastasis 5b. GRANT NUMBER W81XWH-09-1...an important mediator of breast cancer metastasis by driving the epithelial-mesenchymal transition. We find that Twist1 promotes metastasis by

Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

PubMed Central

Vachon, Celine M.; Scott, Christopher G.; Fasching, Peter A.; Hall, Per; Tamimi, Rulla M.; Li, Jingmei; Stone, Jennifer; Apicella, Carmel; Odefrey, Fabrice; Gierach, Gretchen L.; Jud, Sebastian M.; Heusinger, Katharina; Beckmann, Matthias W.; Pollan, Marina; Fernández-Navarro, Pablo; González-Neira, Anna; Benítez, Javier; van Gils, Carla H.; Lokate, Mariëtte; Onland-Moret, N. Charlotte; Peeters, Petra H.M.; Brown, Judith; Leyland, Jean; Varghese, Jajini S.; Easton, Douglas F.; Thompson, Deborah J.; Luben, Robert N.; Warren, Ruth ML; Wareham, Nicholas J.; Loos, Ruth JF; Khaw, Kay-Tee; Ursin, Giske; Lee, Eunjung; Gayther, Simon A.; Ramus, Susan J.; Eeles, Rosalind A.; Leach, Martin O.; Kwan-Lim, Gek; Couch, Fergus J.; Giles, Graham G.; Baglietto, Laura; Krishnan, Kavitha; Southey, Melissa C.; Le Marchand, Loic; Kolonel, Laurence N.; Woolcott, Christy; Maskarinec, Gertraud; Haiman, Christopher A; Walker, Kate; Johnson, Nichola; McCormack, Valerie A.; Biong, Margarethe; Alnæs, Grethe I.G.; Gram, Inger Torhild; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lindström, Sara; Hankinson, Susan E.; Hunter, David J.; Andrulis, Irene L.; Knight, Julia A.; Boyd, Norman F.; Figueroa, Jonine D.; Lissowska, Jolanta; Wesolowska, Ewa; Peplonska, Beata; Bukowska, Agnieszka; Reszka, Edyta; Liu, JianJun; Eriksson, Louise; Czene, Kamila; Audley, Tina; Wu, Anna H.; Pankratz, V. Shane; Hopper, John L.; dos-Santos-Silva, Isabel

2013-01-01

Background Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures. Methods We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status. Results Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07). Conclusion We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland. Impact We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. PMID:22454379

Reduced ING1 levels in breast cancer promotes metastasis.

PubMed

Thakur, Satbir; Singla, Arvind K; Chen, Jie; Tran, Uyen; Yang, Yang; Salazar, Carolina; Magliocco, Anthony; Klimowicz, Alexander; Jirik, Frank; Riabowol, Karl

2014-06-30

INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer.

Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression.

PubMed

Mao, Xiao-Yun; Fan, Chui-Feng; Wei, Jing; Liu, Cong; Zheng, Hua-Chuan; Yao, Fan; Jin, Feng

2011-12-01

N-myc downstream-regulated gene-1 (NDRG1) has been identified as a protein involved in the differentiation of epithelial cells. As a newly metastasis suppressor gene, whether it contributes to carcinogenesis of breast cancer is still unknown. This study aimed to clarify the possible role of NDRG1 for breast cancer carcinogenesis, and further to investigate its clinicopathological significance in invasive breast cancer. We examined the expression of NDRG1 in normal epithelium of breast (n = 35), usual ductal hyperplasia (n = 22), atypical ductal hyperplasia (n = 33), atypical lobular hyperplasia (n = 8), ductal carcinoma in situ (n = 16), lobular carcinoma in situ (n = 6), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 45) by immunohistochemistry and analyzed the correlation between NDRG expression and clinicopathological features of invasive breast cancer. Western blot analysis was carried out to investigate the expression of NDRG1 in 20 invasive ductal breast cancer and the paired non-tumor portion of the same case. NDRG1 expression in invasive breast cancer (70/95, 73.7%) was higher than that in noninvasive breast lesions (29/85, 34.1%; p < 0.05) which was higher than that in normal breast epithelium (5/35, 14.3%; p < 0.05). Statistical analysis revealed a significant correlation between NDRG1 expression with tumor stage in invasive breast cancer, and its expression in invasive ductal carcinoma is significantly higher than invasive lobular carcinoma (p < 0.05). It was not associated with age, menopausal status, tumor size, and lymph node metastasis. NDRG1 protein levels were significantly higher in invasive ductal breast cancer compared to the paired non-tumor portion of the same case by Western blot analysis (p < 0.05). Increased NDRG-1 expression is associated with breast atypia-to-carcinoma progression. NDRG1 expression might participate in the carcinogenesis and progression of invasive

Association of BCSC-1 and MMP-14 with human breast cancer.

PubMed

Di, Dalin; Chen, Lei; Guo, Yingying; Wang, Lina; Wang, Huidong; Ju, Jiyu

2018-04-01

Breast cancer suppressor candidate-1 (BCSC-1) is a candidate tumor suppressor gene that was identified recently. Decreased levels of BCSC-1 have been detected in a variety of cancer types in previous studies. Matrix metalloproteinase (MMP)-14 is a membrane-type MMP that plays an important role in tumor progression and prognosis. Previous research has indicated that MMP-14 is highly expressed in different cancer types and promotes tumor invasion or metastasis by remodeling the extracellular matrix. However, there have been few reports on BCSC-1 and MMP-14 in human breast cancer in recent years. In the present study, the association of BCSC-1 and MMP-14 with human breast cancer was investigated. The immunohistochemical analysis results revealed reduced expression of BCSC-1 and overexpression of MMP-14 in breast cancer tissues compared with adjacent normal breast tissues. Quantitative polymerase chain reaction and western blot analyses also showed that BCSC-1 was expressed at significantly lower levels, and that MMP-14 was expressed at significantly higher levels in breast cancer tissues compared with healthy breast tissue. Furthermore, decreased expression of BCSC-1 and overexpression of MMP-14 were associated with tumor cellular differentiation, lymph node metastasis and distant metastasis. A correlational analysis between BCSC-1 and MMP-14 was also conducted, and the results indicated a negative correlation between the two. In conclusion, the current findings indicate that BCSC-1 is downregulated, while MMP-14 is overexpressed in human breast cancer. These two genes may play important roles during the process of human breast cancer development.

Status of estrogen receptor 1 (ESR1) gene in mastopathy predicts subsequent development of breast cancer.

PubMed

Soysal, Savas D; Kilic, Incken B; Regenbrecht, Christian R A; Schneider, Sandra; Muenst, Simone; Kilic, Nerbil; Güth, Uwe; Dietel, Manfred; Terracciano, Luigi M; Kilic, Ergin

2015-06-01

Mastopathy is a common disease of the breast likely associated with elevated estrogen levels and a putative risk factor for breast cancer. The role of estrogen receptor alpha (ESR1) in mastopathy has not been investigated previously. Here, we investigated the prevalence of ESR1 gene amplification in mastopathy and its prediction for breast cancer. Paraffin-embedded tissues from 58 women with invasive breast cancer were analyzed. For all women, tissues with mastopathy taken at least 1.5 years before first diagnosis of breast cancer were available. Tissue from 46 women with mastopathy without a diagnosis of breast carcinoma in the observed time frame (12-18 years) was used as control. Fluorescence in situ hybridization analysis revealed that ESR1 was amplified in nine of 58 (15.5 %) breast cancers. All ESR1-amplified breast cancers were strongly positive for estrogen receptor with ER immunohistochemistry. Interestingly, in women with ESR1 amplification in breast cancer, the amplification was detectable in mastopathic tissues prior to the first diagnosis of breast cancer but was absent in tissues from women with mastopathy who did not develop breast cancer. Our study suggests that ESR1 gene amplification is an early event in breast pathology and might be a helpful predictive marker to identify patients at high risk of developing breast cancer.

Risk of second primary cancer among women with breast cancer: a population-based study in Granada (Spain).

PubMed

Molina-Montes, Esther; Pollán, Marina; Payer, Tilman; Molina, Elena; Dávila-Arias, Cristina; Sánchez, María-José

2013-08-01

The higher risk of developing new cancers in breast cancer survivors is a public health concern. Our aim was to examine risk of second primary cancers among women diagnosed with breast cancer. We studied two cohorts of female cancer patients identified in a population-based cancer registry in Granada (Spain): women first diagnosed with a primary breast cancer (n=5897) and those with a primary cancer in another site (n=22,814), followed during 1985-2007 for second cancers and breast cancer occurrence, respectively. We used Standardized Incidence Ratios (SIRs) to estimate second cancer risk by age (<50y, ≥50y), time since diagnosis (≤5y, >5y) and calendar periods (≤1995, >1996). SIR for breast cancer was calculated in the second cohort. The risk of developing second cancers (n=314) was 39% higher (95% CI=1.23-1.54) among breast cancer patients, and particularly high among women under 50 (SIR=1.96, 95% CI=1.48-2.44). Excess risk for endometrial cancer (SIR=3.04, 95% CI=2.14-3.94) was statistically significant and remained so in women over 50. Younger women were at higher risk of second ovarian cancer (SIR=4.90, 95% CI=1.27-8.53). Increased SIRs were observed during the first five years after breast cancer diagnosis, whereas SIRs decreased thereafter. Breast cancer incidence (n=171) was not higher among women previously diagnosed with other cancer types (SIR=0.86, 95% CI=0.74-1.00). Women diagnosed with breast cancer have a higher incidence of second primary cancers, particularly of endometrial cancer in women over 50 at diagnosis, and ovarian cancer in younger women. These findings may be explained by treatment-related effects or shared risk factors. Copyright © 2013 Elsevier Inc. All rights reserved.

N-3 Polyunsaturated Fatty Acids of Marine Origin and Multifocality in Human Breast Cancer.

PubMed

Ouldamer, Lobna; Goupille, Caroline; Vildé, Anne; Arbion, Flavie; Body, Gilles; Chevalier, Stephan; Cottier, Jean Philippe; Bougnoux, Philippe

2016-01-01

The microenvironment of breast epithelial tissue may contribute to the clinical expression of breast cancer. Breast epithelial tissue, whether healthy or tumoral, is directly in contact with fat cells, which in turn could influence tumor multifocality. In this pilot study we investigated whether the fatty acid composition of breast adipose tissue differed according to breast cancer focality. Twenty-three consecutive women presenting with non-metastatic breast cancer underwent breast-imaging procedures including Magnetic Resonance Imaging prior to treatment. Breast adipose tissue specimens were collected during breast surgery. We established a biochemical profile of adipose tissue fatty acids by gas chromatography. We assessed whether there were differences according to breast cancer focality. We found that decreased levels in breast adipose tissue of docosahexaenoic and eicosapentaenoic acids, the two main polyunsaturated n-3 fatty acids of marine origin, were associated with multifocality. These differences in lipid content may contribute to mechanisms through which peritumoral adipose tissue fuels breast cancer multifocality.

Methylation status and protein expression of RASSF1A in breast cancer patients.

PubMed

Hagrass, Hoda A; Pasha, Heba F; Shaheen, Mohamed A; Abdel Bary, Eman H; Kassem, Rasha

2014-01-01

Recently genetics and epigenetics alterations have been found to be characteristic of malignancy and hence can be used as targets for detection of neoplasia. RAS association domain family protein 1A (RASSF1A) gene hypermethylation has been a subject of interest in recent researches on cancer breast patients. The aim of the present study was to evaluate whether RASSF1A methylation status and RASSF1A protein expression are associated with the major clinico-pathological parameters. One hundred and twenty breast cancer Egyptian patients and 100-control subjects diagnosed with benign lesions of the breast were enrolled in this study. We evaluated RASSF1A methylation status in tissue and serum samples using Methyl specific PCR together with RASSF1A protein expression in tissues by immunohistochemistry. Results were studied in relation to known prognostic clinicopathological features in breast cancer. Frequency of RASSF1A methylation in tissues and serum were 70 and 63.3 % respectively and RASSF1A protein expression showed frequency of 46.7 %. There was an association between RASSF1A methylation in tissues, serum and loss of protein expression in tissues with invasive carcinoma, advanced stage breast cancer, L.N. metastasis, ER/PR and HER2 negativity. RASSF1A methylation in serum showed high degree of concordance with methylation in tissues (Kappa = 0.851, P < 0.001). RASSF1A hypermethylation in tissues and serum and its protein expression may be a valid, reliable and sensitive tool for detection and follow up of breast cancer patients.

Loss in working years after a breast cancer diagnosis.

PubMed

Plym, Anna; Bower, Hannah; Fredriksson, Irma; Holmberg, Lars; Lambert, Paul C; Lambe, Mats

2018-03-06

Breast cancer can negatively influence working life, but it is unclear how many working years women with breast cancer can expect to lose. Women diagnosed with breast cancer between 1997 and 2012 were identified in the Breast Cancer Data Base Sweden (N=19 661), together with breast cancer-free comparison women (N=81 303). Using flexible parametric survival modelling, the loss in working years was calculated as the difference in the remaining years in the work force between women with and without breast cancer. Women aged 50 years at diagnosis with stage I disease lost on average 0.5 years (95% CI, 0.2-0.7) of their remaining working time; the corresponding estimates were 0.9 years (0.5-1.2) in stage II, 2.5 years (1.9-3.1) in stage III and 8.1 years (6.5-9.7) in stage IV. Women with in situ breast cancer did not lose any working years. The strongest treatment determinant was axillary lymph node dissection. We found a loss in working years not only in late but also in early-stage breast cancer. Although it is reassuring that some groups had no or only a modest work loss, the economic consequences for society are considerable given the large number of women annually diagnosed with breast cancer.

Genetic Polymorphisms of Metastasis Suppressor Gene NME1 and Breast Cancer Survival

PubMed Central

Qu, Shimian; Long, Jirong; Cai, Qiuyin; Shu, Xiao-Ou; Cai, Hui; Gao, Yu-Tang; Zheng, Wei

2009-01-01

Purpose Ample evidence supports an important role of tumor metastasis suppressor genes in cancer metastatic processes. We evaluated the association of genetic polymorphisms of tumor metastasis suppressor gene NME1 with breast cancer prognosis in a follow-up study of patients with primary breast cancer and further investigated the functions of these polymorphisms. Experimental Design NME1 genotypes were analyzed in a cohort of 1134 breast cancer patients recruited as part of the Shanghai Breast Cancer Study who were followed for a median of 7.1 years. In vitro biochemical analyses were carried out to examine the function of NME1 gene polymorphisms. Results Single nucleotide polymorphisms (SNPs) in the promoter region of the NME1 gene were found to be associated with breast cancer prognosis. Patients carrying the C allele in rs16949649 were associated with higher breast cancer-specific mortality (HR =1.4, 95% CI =1.1–1.9) as compared to those carrying the wild-type allele, and the association was more evident in patients with an early stage cancer (HR=1.7, 95% CI =1.2–2.5). SNP rs2302254 was also associated with breast cancer prognosis, and the association was statistically significant for the risk of breast cancer relapse, metastasis, and death (HR=1.3, 95% CI, 1.0–1.6). In vitro biochemical analyses showed that minor alleles in rs2302254 and rs3760468, which is in strong linkage disequilibrium with rs16949646, altered nuclear proteins binding capacity and reduced NME1 promoter activity, supporting the results from an association study of these SNPs with breast cancer survival. Conclusion Promoter polymorphisms in the NME1 gene may alter its expression and influence breast cancer survival. PMID:18676749

Common breast cancer susceptibility loci are associated with triple negative breast cancer

PubMed Central

Stevens, Kristen N.; Vachon, Celine M.; Lee, Adam M.; Slager, Susan; Lesnick, Timothy; Olswold, Curtis; Fasching, Peter A.; Miron, Penelope; Eccles, Diana; Carpenter, Jane E.; Godwin, Andrew K.; Ambrosone, Christine; Winqvist, Robert; Schmidt, Marjanka K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor; Hartmann, Arndt; Beckmann, Matthias W.; Schulz-Wendtland, Rüdiger; Ekici, Arif B.; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Graham, Nikki; Hein, Rebecca; Nickels, Stephan; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Hans-Peter; Konstantopoulou, Irene; Fostira, Florentia; Pectasides, Dimitrios; Dimopoulos, Athanasios M.; Fountzilas, George; Clarke, Christine L.; Balleine, Rosemary; Olson, Janet E.; Fredericksen, Zachary; Diasio, Robert B.; Pathak, Harsh; Ross, Eric; Weaver, JoEllen; Rüdiger, Thomas; Försti, Asta; Dünnebier, Thomas; Ademuyiwa, Foluso; Kulkarni, Swati; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Ko, Yon-Dschun; Van Limbergen, Erik; Janssen, Hilde; Peto, Julian; Fletcher, Olivia; Giles, Graham G.; Baglietto, Laura; Verhoef, Senno; Tomlinson, Ian; Kosma, Veli-Matti; Beesley, Jonathan; Greco, Dario; Blomqvist, Carl; Irwanto, Astrid; Liu, Jianjun; Blows, Fiona M.; Dawson, Sarah-Jane; Margolin, Sara; Mannermaa, Arto; Martin, Nicholas G.; Montgomery, Grant W; Lambrechts, Diether; dos Santos Silva, Isabel; Severi, Gianluca; Hamann, Ute; Pharoah, Paul; Easton, Douglas F.; Chang-Claude, Jenny; Yannoukakos, Drakoulis; Nevanlinna, Heli; Wang, Xianshu; Couch, Fergus J.

2012-01-01

Triple negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiological factors which promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome wide association studies (GWAS) display heterogeneity of effect among breast cancer subtypes as defined by estrogen receptor (ER) and progesterone receptor (PR) status. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple negative breast cancer and 4,978 healthy controls. We identified six single nucleotide polymorphisms (SNPs) significantly associated with risk of triple negative breast cancer, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.11) and rs8100241 (19p13.11). Together, our results provide convincing evidence of genetic susceptibility for triple negative breast cancer. PMID:21844186

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors.

PubMed

Ambrosone, Christine B; Moysich, Kirsten B; Furberg, Helena; Freudenheim, Jo L; Bowman, Elise D; Ahmed, Sabrina; Graham, Saxon; Vena, John E; Shields, Peter G

2003-01-01

Findings from previous studies regarding the association between the CYP17 genotype and breast cancer are inconsistent. We investigated the role of the MspAI genetic polymorphism in the 5' region of CYP17 on risk of breast cancer and as a modifier of reproductive risk factors. Questionnaire and genotyping data were obtained from a population-based, case-control study of premenopausal (n = 182) and postmenopausal (n = 214) European-American Caucasian women in western New York. Cases and controls were frequency matched by age and by county of residence. Odds ratios and 95% confidence intervals were used to estimate relative risks. The CYP17 genotype was not associated with breast cancer risk; however, controls with the A2/A2 genotype (associated with higher estrogens) had earlier menarche and earlier first full-term pregnancy. Premenopausal women with A1/A1 genotypes, but not with A2 alleles, were at significantly decreased risk with late age at menarche (odds ratio = 0.37, 95% confidence interval = 0.14-0.99), and at increased risk with late age at first full-term pregnancy (odds ratio = 4.30, 95% confidence interval = 1.46-12.67) and with use of oral contraceptives (odds ratio = 3.24, 95% confidence interval = 1.08-9.73). Associations were weaker among postmenopausal women. These results suggest that the effects of factors that may alter breast cancer risk through a hormonal mechanism may be less important among premenopausal women with putative higher lifetime exposures to circulating estrogens related to the CYP17 A2 allele.

Relationship of Predicted Risk of Developing Invasive Breast Cancer, as Assessed with Three Models, and Breast Cancer Mortality among Breast Cancer Patients

PubMed Central

Pfeiffer, Ruth M.; Miglioretti, Diana L.; Kerlikowske, Karla; Tice, Jeffery; Vacek, Pamela M.; Gierach, Gretchen L.

2016-01-01

Purpose Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown. Methods Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC) for 37,939 invasive breast cancers (1996–2007), we estimated 5-year breast cancer risk (<1%; 1–1.66%; ≥1.67%) with three models: BCSC 1-year risk model (BCSC-1; adapted to 5-year predictions); Breast Cancer Risk Assessment Tool (BCRAT); and BCSC 5-year risk model (BCSC-5). Breast cancer-specific mortality post-diagnosis (range: 1–13 years; median: 5.4–5.6 years) was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified (35–44; 45–54; 55–69; 70–89 years) models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years. Results Of 6,021 deaths, 2,993 (49.7%) were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk ≥1.67% versus <1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR) = 0.82 (95% CI = 0.75–0.90); BCRAT: HR = 0.72 (95% CI = 0.65–0.81) and BCSC-5: HR = 0.84 (95% CI = 0.75–0.94). Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55–69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35–44 years. Conclusions Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering

Adherence to Guidelines for Breast Surveillance in Breast Cancer Survivors.

PubMed

Ruddy, Kathryn J; Sangaralingham, Lindsey; Freedman, Rachel A; Mougalian, Sarah; Neuman, Heather; Greenberg, Caprice; Jemal, Ahmedin; Duma, Narjust; Haddad, Tufia C; Lemaine, Valerie; Ghosh, Karthik; Hieken, Tina J; Hunt, Katie; Vachon, Celine; Gross, Cary; Shah, Nilay D

2018-05-01

Background: Guidelines recommend annual mammography after curative-intent treatment for breast cancer. The goal of this study was to assess contemporary patterns of breast imaging after breast cancer treatment. Methods: Administrative claims data were used to identify privately insured and Medicare Advantage beneficiaries with nonmetastatic breast cancer who had residual breast tissue (not bilateral mastectomy) after breast surgery between January 2005 and May 2015. We calculated the proportion of patients who had a mammogram, MRI, both, or neither during each of 5 subsequent 13-month periods. Multinomial logistic regression was used to assess associations between patient characteristics, healthcare use, and breast imaging in the first and fifth years after surgery. Results: A total of 27,212 patients were followed for a median of 2.9 years (interquartile range, 1.8-4.6) after definitive breast cancer surgery. In year 1, 78% were screened using mammography alone, 1% using MRI alone, and 8% using both tests; 13% did not undergo either. By year 5, the proportion of the remaining cohort (n=4,790) who had no breast imaging was 19%. Older age was associated with an increased likelihood of mammography and a decreased likelihood of MRI during the first and fifth years. Black race, mastectomy, chemotherapy, and no MRI at baseline were all associated with a decreased likelihood of both types of imaging. Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance breast imaging, particularly as time passes. Understanding factors associated with imaging in cancer survivors may help improve adherence to survivorship care guidelines. Copyright © 2018 by the National Comprehensive Cancer Network.

CD1d-Expressing Breast Cancer Cells Modulate NKT Cell-Mediated Antitumor Immunity in a Murine Model of Breast Cancer Metastasis

PubMed Central

Hix, Laura M.; Shi, Yihui H.; Brutkiewicz, Randy R.; Stein, Paul L.; Wang, Chyung-Ru; Zhang, Ming

2011-01-01

Background Tumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression. Methodology/Principal Findings In this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors. Conclusions/Significance The results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer. PMID:21695190

Older Patients With Early-stage Breast Cancer: Adjuvant Radiation Therapy and Predictive Factors for Cancer-related Death.

PubMed

Nagar, Himanshu; Yan, Weisi; Christos, Paul; Chao, K S Clifford; Nori, Dattatreyudu; Ravi, Akkamma

2017-06-01

Studies have shown that older women are undertreated for breast cancer. Few data are available on cancer-related death in elderly women aged 70 years and older with pathologic stage T1a-b N0 breast cancer and the impact of prognostic factors on cancer-related death. The Surveillance, Epidemiology, and End Results (SEER) database was queried for women aged 70 years or above diagnosed with pT1a or pT1b, N0 breast cancer who underwent breast conservation surgery from 1999 to 2003. The Kaplan-Meier survival analysis was performed to evaluate breast cause-specific survival (CSS) and overall survival (OS), and the log-rank test was employed to compare CSS/OS between different groups of interest. Multivariable analysis (MVA), using Cox proportional hazards regression analysis, was performed to evaluate the independent effect of age, race, stage, grade, ER status, and radiation treatment on CSS. Adjusted hazard ratios were calculated from the MVA and reflect the increased risk of breast cancer death. Competing-risks survival regression was also performed to adjust the univariate and multivariable CSS hazard ratios for the competing event of death due to causes other than breast cancer. Patients aged 85 and above had a greater risk of breast cancer death compared with patients aged 70 to 74 years (referent category) (adjusted hazard ratio [HRs]=1.98). Race had no effect on CSS. Patients with stage T1bN0 breast cancer had a greater risk of breast cancer death compared with stage T1aN0 patients (adjusted HR=1.35; P=0.09). ER negative patients had a greater risk of breast cancer death compared with ER positive patients (adjusted HR=1.59; P<0.017). Patients with higher grade tumors had a greater risk of breast cancer death compared with patients with grade 1 tumors (referent category) (adjusted HRs=1.69 and 2.96 for grade 2 and 3, respectively). Patients who underwent radiation therapy had a lower risk of breast cancer death compared with patients who did not (adjusted HR=0

[PD-L1 expression and PD-1/PD-L1 inhibitors in breast cancer].

PubMed

Monneur, Audrey; Gonçalves, Anthony; Bertucci, François

2018-03-01

The development of immune checkpoints inhibitors represents one of the major recent advances in oncology. Monoclonal antibodies directed against the programmed cell death protein 1 (PD-1) or its ligand (PD-L1) provides durable disease control, particularly in melanoma, lung, kidney, bladder and head and neck cancers. The purpose of this review is to synthesize current data on the expression of PD-L1 in breast cancer and on the preliminary clinical results of PD-1/PD-L1 inhibitors in breast cancer patients. In breast cancer, PD-L1 expression is heterogeneous and is generally associated with the presence of tumor-infiltrating lymphocytes as well as the presence of poor-prognosis factors, such as young age, high grade, ER-negativity, PR-negativity, and HER-2 overexpression, high proliferative index, and aggressive molecular subtypes (triple negative, basal-like, HER-2-overexpressing). Its prognostic value remains controversial when assessed with immunohistochemistry, whereas it seems favorable in triple-negative cancers when assessed at the mRNA level. Early clinical trials with PD-1/PD-L1 inhibitors in breast cancer have shown efficacy in terms of tumor response and/or disease control in refractory metastatic breast cancers, notably in the triple-negative subtype. Many trials are currently underway, both in the metastatic and neo-adjuvant setting. A crucial issue is identification of biomarkers predictive of response to PD-1/PD-L1 inhibitors. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Novel pyrrolopyrimidines as Mps1/TTK kinase inhibitors for breast cancer.

PubMed

Sugimoto, Yasuro; Sawant, Dwitiya B; Fisk, Harold A; Mao, Liguang; Li, Chenglong; Chettiar, Somsundaram; Li, Pui-Kai; Darby, Michael V; Brueggemeier, Robert W

2017-04-01

New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC 50 values ranging from 0.05 to 1.0μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC 50 values from 0.356μM to 0.809μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Breast Cancer in Young Women

PubMed Central

Trogdon, Justin G.; Ekwueme, Donatus U.; Chamiec-Case, Linda; Guy, Gery P.

2018-01-01

Introduction Little is known about the effect of breast cancers on health-related quality of life among women diagnosed between age 18 and 44 years. The goal of this study is to estimate the effect of breast cancer on health state utility by age at diagnosis (18–44 years versus ≥45 years) and by race/ethnicity. Methods The analytic sample, drawn from the 2009 and 2010 Behavioral Risk Factor Surveillance System and analyzed in 2013, included women diagnosed with breast cancer between age 18 and 44 years (n=1,389) and age ≥45 years (n=6,037). Health state utility values were estimated using Healthy Days variables and a published algorithm. Regression analysis was conducted separately by age at diagnosis and race/ethnicity. Results The breast cancer health state utility decrement within 1 year from date of diagnosis was larger for women diagnosed at age 18–44 years than for women diagnosed at age ≥45 years (−0.116 vs −0.070, p<0.05). Within the younger age-at-diagnosis group, Hispanic women 2–4 years after diagnosis had the largest health state utility decrement (−0.221, p<0.01), followed by non-Hispanic white women within 1 year of diagnosis (−0.126, p<0.01). Conclusions This study is the first to report estimates of health state utility values for breast cancer by age at diagnosis and race/ethnicity from a nationwide sample. The results highlight the need for separate quality of life adjustments for women by age at diagnosis and race/ethnicity when conducting cost-effectiveness analysis of breast cancer prevention, detection, and treatment. PMID:26775905

Genetic variation in ERCC1 and XPF genes and breast cancer risk.

PubMed

Pei, X H; Yang, Z; Lv, X Q; Li, H X

2014-03-31

Breast cancer is one of the most frequently diagnosed cancer in women worldwide, and we conducted a case-control study by genotyping seven potentially functional SNPs, three in ERCC1 and four in XPF, in a Chinese population of 417 breast cancer cases and 417 cancer-free controls. Three SNPs in ERCC1 and four SNPs in XPF were genotyped by using the Taqman Universal PCR Master Mix in the GeneAmp(®) PCR System 9700 with Dual 384-Well Sample Block Module, and assays were performed on a 384-well plate on the Sequenom MassARRAY platform. We found that elevated breast cancer risk was associated with those who had a family history of breast cancer and history of breast disease, and those who were over 25 years old at first full-term pregnancy. We found that decreased risk of breast cancer was associated with those who had a history of full-term pregnancies. Compared with the ERCC1 rs11615 T/T genotype, a significantly higher risk of breast cancer was found in the C/C genotype in codominant and dominant models after adjusting for potential risk factors. Similarly, we found that ERCC1 rs3212986 C/C genotype was associated with an increased risk of breast cancer in codominant, dominant and recessive models. Our study indicated that the ERCC1 rs11615 and rs2298881 polymorphisms are associated with breast cancer in a Chinese population. Further studies with large sample size are greatly needed to elucidate the SNPs of ERCC1 and XPF genes in the development of breast cancer.

BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

PubMed Central

Shimizu, Yoshiko; Luk, Hugh; Horio, David; Miron, Penelope; Griswold, Michael; Iglehart, Dirk; Hernandez, Brenda; Killeen, Jeffrey; ElShamy, Wael M.

2012-01-01

Introduction Women with HER2+ or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2+ and/or TN/BL tumors. Methodology/Principal Findings Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/RasV12-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2+ or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. Conclusion/Significance BRCA1-IRIS overexpression triggers aggressive breast tumor formation

Determining Which Patients Require Irradiation of the Supraclavicular Nodal Area After Surgery for N1 Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Jeong Il; Park, Won, E-mail: wonp68@skku.ed; Huh, Seung Jae

2010-11-15

Purpose: We designed this study to determine which patients have a high risk of supraclavicular node recurrence in N1 breast cancer previously treated with surgery but not having received supraclavicular radiation therapy (SCRT) and to identify which patients needed SCRT. Methods and Materials: We performed a retrospective review of 448 pathologic N1 breast cancer patients treated with mastectomy or breast-conserving treatment, but without SCRT, between 1994 and 2003. Mastectomy was performed in 302 patients (67.4%). The median number of axillary nodes dissected was 17 (range, 5-53). Systemic chemotherapy was administered in 443 patients (98.9%), and 144 patients received radiation aftermore » breast-conserving surgery. The median follow-up was 88 months (range, 15-170 months). Results: At follow-up, the treatment failed in 101 patients (22.5%), and 39 patients (8.7%) had supraclavicular node recurrence. Prognostic factors in supraclavicular node recurrence included lymphovascular invasion (p < 0.0001), extracapsular extension (p < 0.0001), the number of involved axillary nodes (p = 0.0003), and the level of involved axillary nodes (p = 0.012) in univariate and multivariate analyses. The total number of prognostic factors correlated well with supraclavicular node recurrence. In the analysis of 5-year supraclavicular node recurrence-free survival, patients with two or more factors showed a significantly higher recurrence rate than did patients with fewer than two factors (96.8% and 72.9%, respectively; p < 0.0001). Conclusions: The prognostic factors associated with supraclavicular node recurrence were lymphovascular invasion, extracapsular extension, and the number and level of involved axillary nodes. Patients with two or more prognostic factors might benefit from SCRT.« less

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

PubMed Central

Lin, Nancy U.; Kidd, John; Allen, Brian A.; Singh, Nanda; Wenstrup, Richard J.; Hartman, Anne-Renee; Winer, Eric P.; Garber, Judy E.

2016-01-01

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define

Life course evolution of body size and breast cancer survival in the E3N cohort.

PubMed

His, Mathilde; Le Guélennec, Marine; Mesrine, Sylvie; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Françoise; Fagherazzi, Guy; Dossus, Laure

2018-04-15

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty and early adulthood and body size trajectories from childhood to adulthood. Self-assessed body size at age 8, at puberty, at age 20-25 and at age 35-40 and trajectories of body size of 4,662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models. Four trajectories of body size were identified (T1 "moderate increase," T2 "stable/low increase," T3 "increase at puberty" and T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 vs. T2 = 1.27; 95% CI = 1.01-1.60) and an increased risk of second invasive cancer event (HR T1 vs. T2 = 1.25; 95% CI = 1.06-1.47). Silhouettes at various ages were not associated with survival. Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. © 2017 UICC.

Breast Cancer Cause Beliefs: Chinese, Korean, and Mexican American Breast Cancer Survivors

PubMed Central

Gonzalez, Patricia; Lim, Jung-Won; Wang-Letzkus, Ming; Flores, Katrina F.; Allen, Kristi M.; Castañeda, Sheila F.; Talavera, Gregory A.

2014-01-01

This study examined causal attribution beliefs about breast cancer and the influence that these beliefs exert on health behavior change among breast cancer survivors (BCS). Focus groups with Chinese (n = 21), Korean (n = 11), and Mexican American (n = 9) BCS recruited through community- and hospital-based support groups were conducted. Interviews were audio-recorded, transcribed verbatim, and translated into English for thematic content analysis. Three themes concerning beliefs about breast cancer cause common to all three groups included (a) stress, (b) diet, and (c) fatalism. Causal beliefs corresponded to behavioral changes with women describing efforts to improve their diet and manage their stress. Ethnic minority BCS adhere to beliefs about what caused their cancer that influence their health behaviors. Providing quality health care to ethnically diverse cancer survivors requires cultural sensitivity to patients’ beliefs about the causes of their cancer and awareness of how beliefs influence patients’ health behaviors post diagnosis. PMID:25001237

Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study.

PubMed

Borgquist, Signe; Giobbie-Hurder, Anita; Ahern, Thomas P; Garber, Judy E; Colleoni, Marco; Láng, István; Debled, Marc; Ejlertsen, Bent; von Moos, Roger; Smith, Ian; Coates, Alan S; Goldhirsch, Aron; Rabaglio, Manuela; Price, Karen N; Gelber, Richard D; Regan, Meredith M; Thürlimann, Beat

2017-04-10

Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these

Low expression of G protein-coupled oestrogen receptor 1 (GPER) is associated with adverse survival of breast cancer patients

PubMed Central

Martin, Stewart G.; Lebot, Marie N.; Sukkarn, Bhudsaban; Ball, Graham; Green, Andrew R.; Rakha, Emad A.; Ellis, Ian O.; Storr, Sarah J.

2018-01-01

G protein-coupled oestrogen receptor 1 (GPER), also called G protein-coupled receptor 30 (GPR30), is attracting considerable attention for its potential role in breast cancer development and progression. Activation by oestrogen (17β-oestradiol; E2) initiates short term, non-genomic, signalling events both in vitro and in vivo. Published literature on the prognostic value of GPER protein expression in breast cancer indicates that further assessment is warranted. We show, using immunohistochemistry on a large cohort of primary invasive breast cancer patients (n=1245), that low protein expression of GPER is not only significantly associated with clinicopathological and molecular features of aggressive behaviour but also significantly associated with adverse survival of breast cancer patients. Furthermore, assessment of GPER mRNA levels in the METABRIC cohort (n=1980) demonstrates that low GPER mRNA expression is significantly associated with adverse survival of breast cancer patients. Using artificial neural networks, genes associated with GPER mRNA expression were identified; these included notch-4 and jagged-1. These results support the prognostic value for determination of GPER expression in breast cancer. PMID:29899833

DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis.

PubMed

Yu, Zhaojin; Xiao, Qinghuan; Zhao, Lin; Ren, Jie; Bai, Xuefeng; Sun, Mingli; Wu, Huizhe; Liu, Xiaojian; Song, Zhiguo; Yan, Yuanyuan; Mi, Xiaoyi; Wang, Enhua; Jin, Feng; Wei, Minjie

2015-09-01

DNA methyltransferases (DNMTs), including DNMT1, 3a, and 3b, play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of DNMTs is associated with the development of breast cancer. This study aimed to explore the clinical significance of DNMT proteins in sporadic breast cancer. We investigated the expression of DNMT1, 3a, and 3b in 256 breast cancer and 36 breast fibroadenoma, using immunohistochemistry. The expression of DNMT1 and 3a was significantly higher in breast cancer than in fibroadenoma. In breast cancer, the expression of DNMT1 was significantly correlated with lymph node metastasis (P = 0.020), and the expression of DNMT3a and 3b was significantly correlated with advanced clinical stages (P = 0.046 and 0.012, respectively). Overexpression of DNMT1/3a was correlated with promoter hypermethylation and reduced expression of ERα and BRCA1. The expression levels of DNMT1 or DNMT3a were associated with a significantly shorter DFS or OS in a subgroup of breast cancer patients (patients with the age ≤50 years old, ERα-negative status, or HER2-postive status). The expression of DNMT1 or a combined expression of DNMT1 and 3a was associated with poor prognosis in patients who received chemotherapy and endocrine therapy, but not in patients who received chemotherapy alone. These findings suggest that DNMT1 and 3a may be involved in the progression and prognosis of sporadic breast cancer. © 2014 Wiley Periodicals, Inc.

BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group.

PubMed Central

Stoppa-Lyonnet, D; Laurent-Puig, P; Essioux, L; Pagès, S; Ithier, G; Ligot, L; Fourquet, A; Salmon, R J; Clough, K B; Pouillart, P; Bonaïti-Pellié, C; Thomas, G

1997-01-01

An account of familial aggregation in breast/ovarian cancer has become possible with the identification of BRCA1 germ-line mutations. We evaluated, for 249 individuals registered with the Institut Curie in Paris, the prior probability that an individual carried a mutation that predisposes to these diseases. We chose 160 women for BRCA1 analysis: 103 with a family history of breast cancer and 57 with a family history of breast-ovarian cancer. To detect small mutations, we generated and analyzed 35 overlapping genomic PCR products that cover the coding portion of the gene, by using denaturing gradient gel electrophoresis. Thirty-eight truncating mutations (32 frameshifts, 4 nonsense mutations, and 2 splice variants) were observed in 15% of women with a family history of breast cancer only and in 40% of those with a history of breast-ovarian cancer. Twelve of 25 distinct truncating mutations identified were novel and unique. Most BRCA1 mutations that had been reported more than five times in the Breast Cancer Information Core were present in our series. One mutation (5149del4) observed in two apparently unrelated families most likely originates from a common ancestor. The position of truncating mutations did not significantly affect the ratio of the risk of breast cancer to that of ovarian cancer. In addition, 15 DNA variants (14 missense mutations and 1 neutral mutation) were identified, 9 of which were novel. Indirect evidence suggests that seven of these mutations are deleterious. Images Figure 2 Figure 3 PMID:9150149

Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study.

PubMed

Kotsopoulos, Joanne; Sukiennicki, Grzegorz; Muszyńska, Magdalena; Gackowski, Daniel; Kąklewski, Krzysztof; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Gronwald, Jacek; Byrski, Tomasz; Ashuryk, Oleg; Dębniak, Tadeusz; Tołoczko-Grabarek, Aleksandra; Stawicka, Małgorzata; Godlewski, Dariusz; Oliński, Ryszard; Jakubowska, Anna; Narod, Steven A; Lubinski, Jan

2012-07-01

Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland. We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients. Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91). This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines.

PubMed

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-04-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS).

PubMed

Andrieu, Nadine; Goldgar, David E; Easton, Douglas F; Rookus, Matti; Brohet, Richard; Antoniou, Antonis C; Peock, Susan; Evans, Gareth; Eccles, Diana; Douglas, Fiona; Noguès, Catherine; Gauthier-Villars, Marion; Chompret, Agnès; Van Leeuwen, Flora E; Kluijt, Irma; Benitez, Javier; Arver, Brita; Olah, Edith; Chang-Claude, Jenny

2006-04-19

Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers. We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided. There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20-24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25-29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; > or = 30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was

Susceptibility to breast cancer and three polymorphisms of GSTZ1.

PubMed

Saadat, Iraj; Khalili, Maryam; Nafissi, Samane; Omidvari, Shahpour; Saadat, Mostafa

2012-03-01

Glutathione S-transferases class zeta (GSTζ) is involved in the detoxification of xenobiotic compounds and catalyzes the biotransformation of a variety of α-haloacids including dichloroacetic acid and chlorofluoroacetic acid. It has been reported that, in mice, deficiency of Gstz1 (a member of GSTζ) resulted in the generation of a constant level of oxidative stress. The present study was carried out to investigate the association between genetic polymorphisms of GSTZ1 (in promoter site G-1002A and in coding sites Glu32Lys and Gly42Arg) and risk of breast cancer. We included 106 females with breast cancer and 106 healthy females frequency matched for age. The study polymorphisms were not associated with risk of breast cancer (p>0.05). The polymorphisms of GSTZ1 showed strong linkage disequilibrium among cancer patients and control subjects (p<0.0001). There was no significant difference between cancer patients and controls for frequencies of the GSTZ1 haplotypes (p>0.05). It seems there is no meaningful relationship between the genetic polymorphisms of GSTZ1 and risk of breast cancer.

Transient SNAIL1 expression is necessary for metastatic competence in breast cancer.

PubMed

Tran, Hung D; Luitel, Krishna; Kim, Michael; Zhang, Kun; Longmore, Gregory D; Tran, David D

2014-11-01

SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis. ©2014 American Association for Cancer Research.

pN0(i+) Breast Cancer: Treatment Patterns, Locoregional Recurrence, and Survival Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karam, Irene; Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, BC; Lesperance, Maria F.

Purpose: To examine treatment patterns, recurrence, and survival outcomes in patients with pN0(i+) breast cancer. Methods and Materials: Subjects were 5999 women with AJCC (6th edition) pT1-3, pN0-N1a, M0 breast cancer diagnosed between 2003 and 2006. Of these, 4342 (72%) had pN0, 96 (2%) had pN0(i+), 349 (6%) had pNmic (micrometastases >0.2 mm to ≤2 mm), and 1212 (20%) had pN1a (1-3 positive macroscopic nodes) disease. Treatment characteristics and 5-year Kaplan-Meier local recurrence, regional recurrence (RR), locoregional recurrence (LRR), and overall survival were compared between nodal subgroups. Multivariable analysis was performed using Cox regression modeling. A 1:3 case-match analysis examinedmore » outcomes in pN0(i+) cases compared with pN0 controls matched for similar tumor and treatment characteristics. Results: Median follow-up was 4.8 years. Adjuvant systemic therapy use increased with nodal stage: 81%, 92%, 95%, and 94% in pN0, pN0(i+), pNmic, and pN1a disease, respectively (P<.001). Nodal radiation therapy (RT) use also increased with nodal stage: 1.7% in pN0, 27% in pN0(i+), 33% in pNmic, and 63% in pN1a cohorts (P<.001). Five-year Kaplan-Meier outcomes in pN0 versus pN0(i+) cases were as follows: local recurrence 1.7% versus 3.7% (P=.20), RR 0.5% versus 2.2% (P=.02), and LRR 2.1% versus 5.8% (P=.02). There were no RR events in 26 patients with pN0(i+) disease who received nodal RT and 2 RR events in 70 patients who did not receive nodal RT. On multivariable analysis, pN0(i+) was not associated with worse locoregional control or survival. On case-match analysis, LRR and overall survival were similar between pN0(i+) and matched pN0 counterparts. Conclusions: Nodal involvement with isolated tumor cells is not a significant prognostic factor for LRR or survival in this study's multivariable and case-match analyses. These data do not support the routine use of nodal RT in the setting of pN0(i+) disease. Prospective studies are needed to define

Breast Cancer in Men

MedlinePlus

FACTS FOR LIFE Breast Cancer in Men Do men get breast cancer? Since men have breast tissue, they can get breast cancer, but it’s rare. About 1 percent of ... breast cancer cases in the U.S. occur in men. It may sound like a small number, but ...

Experimental Therapy of Advanced Breast Cancer: Targeting NFAT1-MDM2-p53 Pathway.

PubMed

Qin, Jiang-Jiang; Wang, Wei; Zhang, Ruiwen

2017-01-01

Advanced breast cancer, especially advanced triple-negative breast cancer, is typically more aggressive and more difficult to treat than other breast cancer phenotypes. There is currently no curable option for breast cancer patients with advanced diseases, highlighting the urgent need for novel treatment strategies. We have recently discovered that the nuclear factor of activated T cells 1 (NFAT1) activates the murine double minute 2 (MDM2) oncogene. Both MDM2 and NFAT1 are overexpressed and constitutively activated in breast cancer, particularly in advanced breast cancer, and contribute to its initiation, progression, and metastasis. MDM2 regulates cancer cell proliferation, cell cycle progression, apoptosis, migration, and invasion through both p53-dependent and -independent mechanisms. We have proposed to target the NFAT1-MDM2-p53 pathway for the treatment of human cancers, especially breast cancer. We have recently identified NFAT1 and MDM2 dual inhibitors that have shown excellent in vitro and in vivo activities against breast cancer, including triple-negative breast cancer. Herein, we summarize recent advances made in the understanding of the oncogenic functions of MDM2 and NFAT1 in breast cancer, as well as current targeting strategies and representative inhibitors. We also propose several strategies for inhibiting the NFAT1-MDM2-p53 pathway, which could be useful for developing more specific and effective inhibitors for breast cancer therapy. Copyright © 2017. Published by Elsevier Inc.

Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1.

PubMed

Xie, Xiayang; Tang, Shou-Ching; Cai, Yafei; Pi, Wenhu; Deng, Libin; Wu, Guangyu; Chavanieu, Alain; Teng, Yong

2016-09-06

Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 (ARF1) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis.

Excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive familial breast cancer cases.

PubMed

Adank, Muriel A; Verhoef, Senno; Oldenburg, Rogier A; Schmidt, Marjanka K; Hooning, Maartje J; Martens, John W M; Broeks, Annegien; Rookus, Matti; Waisfisz, Quinten; Witte, Birgit I; Jonker, Marianne A; Meijers-Heijboer, Hanne

2013-05-01

The CHEK2∗1100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK2∗1100delC mutation within a familial non-BRCA1/2 breast cancer setting. Cancer incidences were compared between first degree relatives of 107 familial breast cancer patients positive for the CHEK2∗1100delC mutation (CHEK2 positive families) and first degree relatives of 314 familial breast cancer patients without the CHEK2∗1100delC mutation (CHEK2 negative families). All families were derived from the same pool of familial non-BRCA1/2 breast cancer families (n=2554). Medical information of 2188 first degree relatives of these families was analysed for cancer risk. CHEK2∗1100delC status of relatives was unknown. Increased breast cancer risk (hazard ratio (HR) 2.0 (95% confidence interval (CI): 1.4-2.7), p<0.001) was observed in sisters of CHEK2∗1100delC positive index cases compared to sisters of CHEK2∗1100delC negative index cases. HR was 1.6 (95% CI: 1.0-2.4) for mothers of CHEK2 positive versus negative index cases (p=0.041). For second primary breast cancers HR was increased in CHEK2∗1100delC positive index cases (HR 2.1, 95% CI: 1.3-3.3, p=0.003) and their sisters (HR 2.6, 95% CI: 1.1-6.1, p=0.025). There is an excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive non-BRCA1/2 familial breast cancer patients compared to non-CHEK2∗1100delC familial breast cancer relatives. Genotyping for the CHEK2∗1100delC mutation in a familial breast cancer setting contributes to optimal clinical surveillance in countries in which this mutation is prevalent. Carriers and female relatives are eligible for stringent breast surveillance programs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Omission of Breast Radiotherapy in Low-risk Luminal A Breast Cancer: Impact on Health Care Costs.

PubMed

Han, K; Yap, M L; Yong, J H E; Mittmann, N; Hoch, J S; Fyles, A W; Warde, P; Gutierrez, E; Lymberiou, T; Foxcroft, S; Liu, F F

2016-09-01

The economic burden of cancer care is substantial, including steep increases in costs for breast cancer management. There is mounting evidence that women age ≥ 60 years with grade I/II T1N0 luminal A (ER/PR+, HER2- and Ki67 ≤ 13%) breast cancer have such low local recurrence rates that adjuvant breast radiotherapy might offer limited value. We aimed to determine the total savings to a publicly funded health care system should omission of radiotherapy become standard of care for these patients. The number of women aged ≥ 60 years who received adjuvant radiotherapy for T1N0 ER+ HER2- breast cancer in Ontario was obtained from the provincial cancer agency. The cost of adjuvant breast radiotherapy was estimated through activity-based costing from a public payer perspective. The total saving was calculated by multiplying the estimated number of luminal A cases that received radiotherapy by the cost of radiotherapy minus Ki-67 testing. In 2010, 748 women age ≥ 60 years underwent surgery for pT1N0 ER+ HER2- breast cancer; 539 (72%) underwent adjuvant radiotherapy, of whom 329 were estimated to be grade I/II luminal A subtype. The cost of adjuvant breast radiotherapy per case was estimated at $6135.85; the cost of Ki-67 at $114.71. This translated into an annual saving of about $2.0million if radiotherapy was omitted for all low-risk luminal A breast cancer patients in Ontario and $5.1million across Canada. There will be significant savings to the health care system should omission of radiotherapy become standard practice for women with low-risk luminal A breast cancer. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Genetic and small molecule inhibition of arylamine N-acetyltransferase 1 reduces anchorage-independent growth in human breast cancer cell line MDA-MB-231.

PubMed

Stepp, Marcus W; Doll, Mark A; Carlisle, Samantha M; States, J Christopher; Hein, David W

2018-04-01

Arylamine N-acetyltransferase 1 (NAT1) expression is reported to affect proliferation, invasiveness, and growth of cancer cells. MDA-MB-231 breast cancer cells were engineered such that NAT1 expression was elevated or suppressed, or treated with a small molecule inhibitor of NAT1. The MDA-MB-231 human breast cancer cell lines were engineered with a scrambled shRNA, a NAT1 specific shRNA or a NAT1 overexpression cassette stably integrated into a single flippase recognition target (FRT) site facilitating incorporation of these different genetic elements into the same genomic location. NAT1-specific shRNA reduced NAT1 activity in vitro by 39%, increased endogenous acetyl coenzyme A levels by 35%, and reduced anchorage-independent growth (sevenfold) without significant effects on cell morphology, growth rates, anchorage-dependent colony formation, or invasiveness compared to the scrambled shRNA cell line. Despite 12-fold overexpression of NAT1 activity in the NAT1 overexpression cassette transfected MDA-MB-231 cell line, doubling time, anchorage-dependent cell growth, anchorage-independent cell growth, and relative invasiveness were not changed significantly when compared to the scrambled shRNA cell line. A small molecule (5E)-[5-(4-hydroxy-3,5-diiodobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (5-HDST) was 25-fold more selective towards the inhibition of recombinant human NAT1 than N-acetyltransferase 2. Incubation of MDA-MB-231 cell line with 5-HDST resulted in 60% reduction in NAT1 activity and significant decreases in cell growth, anchorage-dependent growth, and anchorage-independent growth. In summary, inhibition of NAT1 activity by either shRNA or 5-HDST reduced anchorage-independent growth in the MDA-MB-231 human breast cancer cell line. These findings suggest that human NAT1 could serve as a target for the prevention and/or treatment of breast cancer. © 2018 Wiley Periodicals, Inc.

FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yi; Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu; Xie, Xiaoyan

Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cellmore » lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.« less

Correlation of SASH1 expression and ultrasonographic features in breast cancer.

PubMed

Gong, Xuchu; Wu, Jinna; Wu, Jian; Liu, Jun; Gu, Hailin; Shen, Hao

2017-01-01

SASH1 is a member of the SH3/SAM adapter molecules family and has been identified as a new tumor suppressor and critical protein in signal transduction. An ectopic expression of SASH1 is associated with decreased cell viability of breast cancer. The aim of this study was to explore the association between SASH1 expression and the ultrasonographic features in breast cancer. A total of 186 patients diagnosed with breast cancer were included in this study. The patients received preoperative ultrasound examination, and the expression of SASH1 was determined using immunohistochemistry methods. Spearman's rank correlation analysis was used to analyze the correlation between SASH1-positive expression and the ultrasonographic features. The positive expression of SASH1 was observed in 63 (33.9%) patients. The positive expression rate of SASH1 was significantly decreased in patients with breast cancer (63/186, 33.9%) compared with controls ( P <0.001). The positive expression rate of SASH1 was significantly decreased in patients with edge burr sign ( P =0.025), lymph node metastasis ( P =0.007), and a blood flow grade of III ( P =0.013) compared with patients without those adverse ultrasonographic features. The expression of SASH1 was negatively correlated with edge burr sign ( P =0.025), lymph node metastasis ( P =0.007), and blood flow grade ( P =0.003) of the patients with breast cancer. The expression of SASH1 was inversely correlated with some critical ultrasonographic features, including edge burr sign, lymph node metastasis, and blood flow grade in breast cancer, and decreased SASH1 expression appears to be associated with adverse clinical and imaging features in breast cancer.

Hypermethylation of the breast cancer-associated gene 1 promoter does not predict cytologic atypia or correlate with surrogate end points of breast cancer risk.

PubMed

Bean, Gregory R; Ibarra Drendall, Catherine; Goldenberg, Vanessa K; Baker, Joseph C; Troch, Michelle M; Paisie, Carolyn; Wilke, Lee G; Yee, Lisa; Marcom, Paul K; Kimler, Bruce F; Fabian, Carol J; Zalles, Carola M; Broadwater, Gloria; Scott, Victoria; Seewaldt, Victoria L

2007-01-01

Mutation of the breast cancer-associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide -150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood 1 promoter hypermethylation was not associated with (a) family history of breast or ovarian cancer or (b) calculated Gail or BRCAPRO risk score. BRCA1 promoter hypermethylation was associated with (a) age (P = 0.028) and (b) the combined frequency of promoter hypermethylation of the retinoic acid receptor-beta2 (RARB) gene, estrogen receptor-alpha (ESR1) gene, and p16 (INK4A) gene (P = 0.003). These observations show that BRCA1 promoter hypermethylation (a) is not associated with breast cancer risk as measured by mathematical risk models and (b) does not predict mammary atypia in RPFNA cytologic samples obtained from high-risk women.

Breast cancer, heterocyclic aromatic amines from meat and N-acetyltransferase 2 genotype.

PubMed

Delfino, R J; Sinha, R; Smith, C; West, J; White, E; Lin, H J; Liao, S Y; Gim, J S; Ma, H L; Butler, J; Anton-Culver, H

2000-04-01

Breast cancer risk has been hypothesized to increase with exposure to heterocyclic aromatic amines (HAAs) formed from cooking meat at high temperature. HAAs require enzymatic activation to bind to DNA and initiate carcinogenesis. N-acetyltransferase 2 (NAT2) enzyme activity may play a role, its rate determined by a polymorphic gene. We examined the effect of NAT2 genetic polymorphisms on breast cancer risk from exposure to meat by cooking method, doneness and estimated HAA [2-amino-1-methyl-6-phenylimidazole[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)] intake. Women were recruited with suspicious breast masses and questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. For 114 cases with breast cancer and 280 controls with benign breast disease, NAT2 genotype was determined using allele-specific PCR amplification to detect slow acetylator mutations. HAAs were estimated from interview data on meat type, cooking method and doneness, combined with a quantitative HAA database. Logistic regression models controlled for known risk factors, first including all controls, then 108 with no or low risk (normal breast or no hyperplasia) and finally 149 with high risk (hyperplasia, atypical hyperplasia, complex fibroadenomas). Meat effects were examined within NAT2 strata to assess interactions. We found no association between NAT2 and breast cancer. These Californian women ate more white than red meat (control median 46 versus 8 g/day). There were no significant associations of breast cancer with red meat for any doneness. White meat was significantly protective (>67 versus <26 g/day, OR 0.46, 95% CI 0.23-0.94, P for trend = 0.02), as was chicken, including well done, pan fried and barbecued chicken. MeIQx and DiMeIQx were not associated with breast cancer. A protective effect of PhIP was confounded after controlling for well done chicken

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines

PubMed Central

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-01-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. PMID:25627111

Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1.

PubMed

Xu, Zhaowei; Yang, Yangyang; Li, Bowen; Li, Yanan; Xia, Kangkai; Yang, Yuxi; Li, Xiahui; Wang, Miao; Li, Shujing; Wu, Huijian

2018-05-11

Breast cancer is a highly heterogeneous carcinoma in women worldwide, but the underlying mechanisms that account for breast cancer initiation and development have not been fully established. Mounting evidence indicates that Checkpoint suppressor 1 (CHES1) is tightly associated with tumorigenesis and prognosis in many types of cancer. However, the definitive function of CHES1 in breast cancer remains to be explored. Here we showed that CHES1 had a physical interaction with estrogen receptor-α (ERα) and repressed the transactivation of ERα in breast cancer cells. Mechanistically, the interaction between CHES1 and ERα enhanced the recruitment of nicotinamide adenine dinucleotide (NAD+) deacetylase Sirtuin 1 (SIRT1), and it further induced SIRT1-mediated ERα deacetylation and repression on the promoter-binding enrichment of ERα. In addition, we also found that the expression of CHES1 was repressed by estrogen-ERα signaling and the expression level of CHES1 was significantly downregulated in ERα-positive breast cancer. The detailed mechanism was that ERα may directly bind to CHES1 potential promoter via recognizing the conserved estrogen response element (ERE) motif in response to estrogen stimulation. Functionally, CHES1 inhibited ERα-mediated proliferation and tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these results identified a negative cross-regulatory loop between ERα and CHES1 that was required for growth of breast cancer cells, it might uncover novel insight into molecular mechanism of CHES1 involved in breast cancer and provide new avenues for molecular-targeted therapy in hormone-regulated breast cancer.

Targeting Sphingosine-1-Phosphate Axis in Obesity-Promoted Breast Cancer

DTIC Science & Technology

2016-05-01

AWARD NUMBER: W81XWH-14-1-0071 TITLE: Targeting Sphingosine-1-Phosphate Axis in Obesity -Promoted Breast Cancer PRINCIPAL INVESTIGATOR...5a. CONTRACT NUMBER Targeting Sphingosine-1-Phosphate Axis in Obesity -Promoted Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0071 5c. PROGRAM ELEMENT...13. SUPPLEMENTARY NOTES 14. ABSTRACT Obesity , which induces low-grade inflammation, is a known risk factor for worse prognosis in many cancers

Olaparib In Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-27

Metastatic Breast Cancer; Invasive Breast Cancer; Somatic Mutation Breast Cancer (BRCA1); Somatic Mutation Breast Cancer (BRCA2); CHEK2 Gene Mutation; ATM Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; BRIP1 Gene Mutation; NBN Gene Mutation

Can we prevent BRCA1-associated breast cancer by RANKL inhibition?

PubMed

Kotsopoulos, Joanne; Singer, Christian; Narod, Steven A

2017-01-01

BRCA1 mutation carriers face a high lifetime risk of breast cancer, estimated at 60 % compared to 10 % in the general population. BRCA1 breast cancers typically have an aggressive course (i.e., high-grade, triple-negative) and are associated with a poor prognosis. At present, primary prevention is limited to prophylactic removal of the unaffected breasts. Effective chemopreventive strategies are not yet available. Emerging evidence suggests that BRCA1 mutation carriers have high circulating levels of progesterone which may play a role in their susceptibility to breast cancer. Recently, the RANK/RANKL system was found to be dysregulated in women with a BRCA1 mutation. Mutation carriers had significantly lower endogenous levels of osteoprotegerin (OPG) than women without a BRCA1 mutation. OPG is an endogenous decoy receptor for RANKL and inhibits RANKL-mediated signaling. RANKL binds to RANK on mammary epithelial cells and stimulates their proliferation and maturation. Low OPG levels may contribute to mammary tumorigenesis through increased proliferation and may explain in part the increased breast cancer risk in BRCA1 mutation carriers. Denosumab is an anti-RANKL monoclonal antibody which is approved to treat osteoporosis and to prevent skeletal damage caused by bone metastases. The emerging role of aberrant RANK-signaling in BRCA1 tumorigenesis suggests that targeting of RANKL may prevent breast cancer among women with germline BRCA1 mutations. Clinical investigations of denosumab are warranted and may lead to a novel chemopreventive approach for breast cancer for high-risk women.

Promoter methylation assay of SASH1 gene in breast cancer.

PubMed

Sheyu, Lin; Hui, Liu; Junyu, Zhang; Jiawei, Xu; Honglian, Wang; Qing, Sang; Hengwei, Zhang; Xuhui, Guo; Qinghe, Xing; Lin, He

2013-01-01

To analyze the relationship between the expression of SASH1 and its methylation level of SASH1 gene promoter in human breast cancer. Expression levels of SASH1 were examined in breast cancer tissues and adjacent normal tissues with immunohistochemistry and with real time PCR (RT-PCR) methylation analysis was performed with MassArray. Immunohistochemistry showed that SASH1 expression was strongly reduced in breast cancer compared with adjacent normal tissues. Quantitative methylation analysis by MassArray revealed that CpG sites in SASH1 promoter shared similar methylation pattern in tumor tissue and adjacent normal tissue. The CpG sites with significant difference in methylation level were CpG_26.27 and CpG_54.55. Moreover, 5-aza-2'-deoxycytidine (5-Aza-dc) treatment of tumor cell line MDA-MB-231 caused significant elevation of SASH1 mRNA. Based on these data, we propose that increase of DNA methylation level in the promoter region of gene SASH1, particularly CpG_26.27 or CpG_54.55 sites, possibly repressed SASH1 expression in breast cancer.

Association between US features of primary tumor and axillary lymph node metastasis in patients with clinical T1-T2N0 breast cancer.

PubMed

Bae, Min Sun; Shin, Sung Ui; Song, Sung Eun; Ryu, Han Suk; Han, Wonshik; Moon, Woo Kyung

2018-04-01

Background Most patients with early-stage breast cancer have clinically negative lymph nodes (LNs). However, 15-20% of patients have axillary nodal metastasis based on the sentinel LN biopsy. Purpose To assess whether ultrasound (US) features of a primary tumor are associated with axillary LN metastasis in patients with clinical T1-T2N0 breast cancer. Material and Methods This retrospective study included 138 consecutive patients (median age = 51 years; age range = 27-78 years) who underwent breast surgery with axillary LN evaluation for clinically node-negative T1-T2 breast cancer. Three radiologists blinded to the axillary surgery results independently reviewed the US images. Tumor distance from the skin and distance from the nipple were determined based on the US report. Association between US features of a breast tumor and axillary LN metastasis was assessed using a multivariate logistic regression model after controlling for clinicopathologic variables. Results Of the 138 patients, 28 (20.3%) had nodal metastasis. At univariate analysis, tumor distance from the skin ( P = 0.019), tumor size on US ( P = 0.023), calcifications ( P = 0.036), architectural distortion ( P = 0.001), and lymphovascular invasion ( P = 0.049) were associated with axillary LN metastasis. At multivariate analysis, shorter skin-to-tumor distance (odds ratio [OR] = 4.15; 95% confidence interval [CI] = 1.01-16.19; P = 0.040) and masses with associated architectural distortion (OR = 3.80; 95% CI = 1.57-9.19; P = 0.003) were independent predictors of axillary LN metastasis. Conclusion US features of breast cancer can be promising factors associated with axillary LN metastasis in patients with clinically node-negative early-stage breast cancer.

High-density lipoprotein of patients with breast cancer complicated with type 2 diabetes mellitus promotes cancer cells adhesion to vascular endothelium via ICAM-1 and VCAM-1 upregulation.

PubMed

Huang, Xiaoqin; He, Dan; Ming, Jia; He, Yubin; Zhou, Champion; Ren, Hui; He, Xin; Wang, Chenguang; Jin, Jingru; Ji, Liang; Willard, Belinda; Pan, Bing; Zheng, Lemin

2016-02-01

Adhesion of disseminating tumor cells to vascular endothelium is a pivotal starting point in the metastasis cascade. We have shown previously that diabetic high-density lipoprotein (HDL) has the capability of promoting breast cancer metastasis, and this report summarizes our more recent work studying the role of abnormal HDL in facilitating the adhesion of the circulating tumor cells to the endothelium. This is an initiating step in breast cancer metastasis, and this work assesses the role of ICAM-1 and VCAM-1 in this process. MDA-MB-231, MCF 7, and human umbilical vein endothelial cells (HUVECs) were treated with normal HDL from healthy controls (N-HDL), HDL from breast cancer patients (B-HDL), or HDL from breast cancer patients complicated with type 2 diabetes mellitus (BD-HDL), and the cell adhesion abilities were determined. ICAM-1 and VCAM-1 expression as well as the protein kinase C (PKC) activity were evaluated. The effect of PKC inhibitor and PKC siRNA on adhesion was also studied. The immunohistochemical staining of ICAM-1, VCAM-1, and E-selectin from breast cancer patients and breast cancer patients complicated with type 2 diabetes mellitus (T2DM) were examined. Our results indicate that BD-HDL promoted an increase in breast cancer cell adhesion to HUVECs and stimulated higher ICAM-1 and VCAM-1 expression on the cells surface of both breast cancer and HUVEC cells, along with the activation of PKC. Increased tumor cell (TC)-HUVEC adhesion, as well as ICAM-1 and VCAM-1 expression induced by BD-HDL, could be inhibited by staurosporine and PKC siRNA. In addition, a Db/db type 2 diabetes mouse model has more TC-Vascular Endothelium adhesion compared to a normal model. However, BD patients have a lower expression of ICAM-1, VCAM-1, and E-selectin in their tumor tissues. BD-HDL facilitates the adhesion of tumor cells to vascular endothelium by upregulating the expression of ICAM-1 and VCAM-1, thereby promoting the initial progression of breast cancer metastasis

Correlation of SASH1 expression and ultrasonographic features in breast cancer

PubMed Central

Gong, Xuchu; Wu, Jinna; Wu, Jian; Liu, Jun; Gu, Hailin; Shen, Hao

2017-01-01

Objective SASH1 is a member of the SH3/SAM adapter molecules family and has been identified as a new tumor suppressor and critical protein in signal transduction. An ectopic expression of SASH1 is associated with decreased cell viability of breast cancer. The aim of this study was to explore the association between SASH1 expression and the ultrasonographic features in breast cancer. Patients and methods A total of 186 patients diagnosed with breast cancer were included in this study. The patients received preoperative ultrasound examination, and the expression of SASH1 was determined using immunohistochemistry methods. Spearman’s rank correlation analysis was used to analyze the correlation between SASH1-positive expression and the ultrasonographic features. Results The positive expression of SASH1 was observed in 63 (33.9%) patients. The positive expression rate of SASH1 was significantly decreased in patients with breast cancer (63/186, 33.9%) compared with controls (P<0.001). The positive expression rate of SASH1 was significantly decreased in patients with edge burr sign (P=0.025), lymph node metastasis (P=0.007), and a blood flow grade of III (P=0.013) compared with patients without those adverse ultrasonographic features. The expression of SASH1 was negatively correlated with edge burr sign (P=0.025), lymph node metastasis (P=0.007), and blood flow grade (P=0.003) of the patients with breast cancer. Conclusion The expression of SASH1 was inversely correlated with some critical ultrasonographic features, including edge burr sign, lymph node metastasis, and blood flow grade in breast cancer, and decreased SASH1 expression appears to be associated with adverse clinical and imaging features in breast cancer. PMID:28138250

Challenging metastatic breast cancer with the natural defensin PvD1.

PubMed

Figueira, Tiago N; Oliveira, Filipa D; Almeida, Inês; Mello, Érica O; Gomes, Valdirene M; Castanho, Miguel A R B; Gaspar, Diana

2017-11-09

Metastatic breast cancer is a very serious life threatening condition that poses many challenges for the pharmaceutical development of effective chemotherapeutics. As the therapeutics targeted to the localized masses in breast improve, metastatic lesions in the brain slowly increase in their incidence compromising successful treatment outcomes overall. The blood-brain-barrier (BBB) is one important obstacle for the management of breast cancer brain metastases. New therapeutic approaches are in demand for overcoming the BBB's breaching by breast tumor cells. In this work we demonstrate the potential dual role of a natural antimicrobial plant defensin, PvD 1 : it interferes with the formation of solid tumors in the breast and concomitantly controls adhesion of breast cancer cells to human brain endothelial cells. We have used a combination of techniques that probe PvD 1 's effect at the single cell level and reveal that this peptide can effectively damage breast tumor cells, leaving healthy breast and brain cells unaffected. Results suggest that PvD1 quickly internalizes in cancer cells but remains located in the membrane of normal cells with no significant damage to its structure and biomechanical properties. These interactions in turn modulate cell adhesiveness between tumor and BBB cells. PvD 1 is a potential template for the design of innovative pharmacological approaches for metastatic breast cancer treatment: the manipulation of the biomechanical properties of tumor cells that ultimately prevent their attachment to the BBB.

Plasma MMP1 and MMP8 expression in breast cancer: Protective role of MMP8 against lymph node metastasis

PubMed Central

Decock, Julie; Hendrickx, Wouter; Vanleeuw, Ulla; Van Belle, Vanya; Van Huffel, Sabine; Christiaens, Marie-Rose; Ye, Shu; Paridaens, Robert

2008-01-01

Background Elevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer. Methods A total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics. Results Median plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis. Conclusion In summary, we observed differences in MMP1 and MMP8 plasma

[Clinicopathological analyses of accessory breast cancer: a report of 22 cases].

PubMed

Wang, Haotian; Duan, Jingjing; Xin, Fei; Cao, Xuchen

2015-01-27

To explore the clinicopathological characteristics, diagnosis, multi-disciplinary therapy and prognosis of accessory breast cancer. The clinical data were retrospectively analyzed for 22 patients with accessory breast cancer from December 2000 and September 2013. Three patients underwent breast-conserving local wide excision of tumor plus axillary lymph node dissection while the remainder had Auchincloss or Halsted mastectomy. The most common histological type was infiltrating ductal carcinoma (n = 16, 72%) and one of them was associated with mucous adenocarcinoma. There were carcinoma simplex (n = 1), papillary adenocarcinoma (n = 1) and adenocarcinoma (n = 4). The most common pathological stages (according to AJCC Staging of Breast Cancer, 2002, 6th edition) were II (n = 15, 68%),I(n = 3), III (n = 4) and IV (n = 0). The median follow-up period was 3 (1-14) years. And the follow-up rate was 100%.Until October 2014, 2 patients died from metastasis and the remainder survived. Accessory breast cancer is rare and has a worse prognosis.Now the clinical diagnostic criteria to it remains controversial and the diagnosis is often late. A definite diagnosis is made on the basis of clinical characteristics, postoperative pathology and imaging examinations. And surgery remains a major option.

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

PubMed

Wang, Xianshu; Pankratz, V Shane; Fredericksen, Zachary; Tarrell, Robert; Karaus, Mary; McGuffog, Lesley; Pharaoh, Paul D P; Ponder, Bruce A J; Dunning, Alison M; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Sinilnikova, Olga M; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Houdayer, Claude; Hogervorst, Frans B L; Hooning, Maartje J; Ligtenberg, Marjolijn J; Spurdle, Amanda; Chenevix-Trench, Georgia; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Singer, Christian F; Gschwantler-Kaulich, Daphne; Dressler, Catherina; Fink, Anneliese; Szabo, Csilla I; Zikan, Michal; Foretova, Lenka; Claes, Kathleen; Thomas, Gilles; Hoover, Robert N; Hunter, David J; Chanock, Stephen J; Easton, Douglas F; Antoniou, Antonis C; Couch, Fergus J

2010-07-15

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer.

PubMed

Weischer, Maren; Nordestgaard, Børge G; Pharoah, Paul; Bolla, Manjeet K; Nevanlinna, Heli; Van't Veer, Laura J; Garcia-Closas, Montserrat; Hopper, John L; Hall, Per; Andrulis, Irene L; Devilee, Peter; Fasching, Peter A; Anton-Culver, Hoda; Lambrechts, Diether; Hooning, Maartje; Cox, Angela; Giles, Graham G; Burwinkel, Barbara; Lindblom, Annika; Couch, Fergus J; Mannermaa, Arto; Grenaker Alnæs, Grethe; John, Esther M; Dörk, Thilo; Flyger, Henrik; Dunning, Alison M; Wang, Qin; Muranen, Taru A; van Hien, Richard; Figueroa, Jonine; Southey, Melissa C; Czene, Kamila; Knight, Julia A; Tollenaar, Rob A E M; Beckmann, Matthias W; Ziogas, Argyrios; Christiaens, Marie-Rose; Collée, Johanna Margriet; Reed, Malcolm W R; Severi, Gianluca; Marme, Frederik; Margolin, Sara; Olson, Janet E; Kosma, Veli-Matti; Kristensen, Vessela N; Miron, Alexander; Bogdanova, Natalia; Shah, Mitul; Blomqvist, Carl; Broeks, Annegien; Sherman, Mark; Phillips, Kelly-Anne; Li, Jingmei; Liu, Jianjun; Glendon, Gord; Seynaeve, Caroline; Ekici, Arif B; Leunen, Karin; Kriege, Mieke; Cross, Simon S; Baglietto, Laura; Sohn, Christof; Wang, Xianshu; Kataja, Vesa; Børresen-Dale, Anne-Lise; Meyer, Andreas; Easton, Douglas F; Schmidt, Marjanka K; Bojesen, Stig E

2012-12-10

We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

PubMed Central

Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

2018-01-01

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

Factors associated with breast MRI use among women with a family history of breast cancer.

PubMed

White, Mary C; Soman, Ashwini; Weinberg, Clarice R; Rodriguez, Juan L; Sabatino, Susan A; Peipins, Lucy A; DeRoo, Lisa; Nichols, Hazel B; Hodgson, M Elizabeth; Sandler, Dale P

2018-05-20

Although annual breast magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer as an adjunct to screening mammography, breast MRI use remains low. We examined factors associated with breast MRI use in a cohort of women with a family history of breast cancer but no personal cancer history. Study participants came from the Sister Study cohort, a nationwide, prospective study of women with at least 1 sister who had been diagnosed with breast cancer but who themselves had not ever had breast cancer (n = 17 894). Participants were surveyed on breast cancer beliefs, cancer worry, breast MRI use, provider communication, and genetic counseling and testing. Logistic regression was used to assess factors associated with having a breast MRI overall and for those at high risk. Breast MRI was reported by 16.1% and was more common among younger women and those with higher incomes. After adjustment for demographics, ever use of breast MRI was associated with actual and perceived risk. Odds ratios (OR) were 12.29 (95% CI, 8.85-17.06), 2.48 (95% CI, 2.27-2.71), and 2.50 (95% CI, 2.09-2.99) for positive BRCA1/2 test, lifetime breast cancer risk ≥ 20%, and being told by a health care provider of higher risk, respectively. Women who believed they had much higher risk than others or had higher level of worry were twice as likely to have had breast MRI; OR = 2.23 (95% CI, 1.82-2.75) and OR = 1.76 (95% CI, 1.52-2.04). Patterns were similar among women at high risk. Breast cancer risk, provider communication, and personal beliefs were determinants of breast MRI use. To support shared decisions about the use of breast MRI, women could benefit from improved understanding of the chances of getting breast cancer and increased quality of provider communications. © 2018 Wiley Periodicals, Inc.

Benign Breast Disease, Mammographic Breast Density, and the Risk of Breast Cancer

PubMed Central

2013-01-01

Background Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. Methods We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Results Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Conclusions Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis. PMID:23744877

Benign breast disease, mammographic breast density, and the risk of breast cancer.

PubMed

Tice, Jeffrey A; O'Meara, Ellen S; Weaver, Donald L; Vachon, Celine; Ballard-Barbash, Rachel; Kerlikowske, Karla

2013-07-17

Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.

A prospective study of XRCC1 haplotypes and their interaction with plasma carotenoids on breast cancer risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohrenweiser, H W; Han, J; Hankinson, S E

2004-01-15

The XRCC1 protein is involved in the base excision repair pathway through interactions with other proteins. Polymorphisms in the XRCC1 gene may lead to variation in repair proficiency and confer inherited predisposition to cancer. We prospectively assessed the associations between polymorphisms and haplotypes in XRCC1 and breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n 1004; controls, n 1385). We further investigated gene-environment interactions between the XRCC1 variations and plasma carotenoids on breast cancer risk. We genotyped four haplotype-tagging single nucleotide polymorphisms Arg {sup 194}Trp, C26602T, Arg{sup 399}Gln, and Gln{sup 632}Gln in themore » XRCC1 gene. Five common haplotypes accounted for 99% of the chromosomes in the present study population of mostly Caucasian women. We observed a marginally significant reduction in the risk of breast cancer among {sup 194}Trp carriers. As compared with no-carriers, women with at least one {sup 194}Trp allele had a multivariate odds ratio of 0.79 (95% of the confidence interval, 0.60 -1.04). The inferred haplotype harboring the {sup 194}Trp allele was more common in controls than in cases (6.6 versus 5.3%, P 0.07). We observed that the Arg {sup 194}Trp modified the inverse associations of plasma -carotene level (P, ordinal test for interaction 0.02) and plasma -carotene level (P, ordinal test for interaction 0.003) with breast cancer risk. No suggestion of an interaction was observed between the Arg {sup 194}Trp and cigarette smoking. Our results suggest an inverse association between XRCC1 {sup 194}Trp allele and breast cancer risk. The findings of the effect modification of the Arg {sup 194}Trp on the relations of plasma -and -carotene levels with breast cancer risk suggest a potential protective effect of carotenoids in breast carcinogenesis by preventing oxidative DNA damage.« less

Survival in Norwegian BRCA1 mutation carriers with breast cancer.

PubMed

Hagen, Anne Irene; Tretli, Steinar; Maehle, Lovise; Apold, Jaran; Vedå, Nina; Møller, Pål

2009-04-14

Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers.One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival.BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls.Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis.

Survival in Norwegian BRCA1 mutation carriers with breast cancer

PubMed Central

Hagen, Anne Irene; Tretli, Steinar; Mæhle, Lovise; Apold, Jaran; Vedå, Nina; Møller, Pål

2009-01-01

Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers. One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival. BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls. Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis. PMID:19366445

Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

PubMed Central

Cyr-Depauw, Chanèle; Northey, Jason J.; Tabariès, Sébastien; Annis, Matthew G.; Dong, Zhifeng; Cory, Sean; Hallett, Michael; Rennhack, Jonathan P.; Andrechek, Eran R.

2016-01-01

ShcA is an important mediator of ErbB2- and transforming growth factor β (TGF-β)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-β stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling. PMID:26976638

Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1

PubMed Central

Cantor, Sharon B; Guillemette, Shawna

2011-01-01

It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1–FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression. PMID:21345144

RING1 and YY1 binding protein suppresses breast cancer growth and metastasis.

PubMed

Zhou, Hongyan; Li, Jie; Zhang, Zhanqiang; Ye, Runyi; Shao, Nan; Cheang, Tuckyun; Wang, Shenming

2016-12-01

Evidence suggests that RING1 and YY1 binding protein (RYBP) functions as a tumor suppressor. However, its role in breast cancer remains unclear. In the present study, the expression of RYBP was assessed in breast cancer patients and cell lines. Disease-free survival durations of breast cancer patients with high RYBP expression were determined based on the ATCG dataset. The effects of RYBP overexpression on cell growth, migration and invasive potency were also assessed. Nude mouse xenograft and lung metastasis models were also used to confirm the role of RYBP. The involvement of SRRM3 in RYBP-mediated breast cancer suppression was explored using SRRM3 siRNA. The potential relationship between RYBP, SRRM3, and REST-003 was examined by qPCR. The results showed that RYBP was downregulated in breast cancer patients and in several breast cancer cell lines. Breast cancer patients with high expression levels of RYBP displayed better disease-free survival. Overexpression of RYBP in MDA-MB-231 and SK-BR-3 cells significantly decreased cell proliferation, migration, and invasion ability, and increased the proportion of cells arrested in S-phase compared with the negative control cells. Additionally, upregulation of proliferation-related cell cycle proteins (cyclin A and cyclin B1) and E-cadherin, and downregulation of snail were observed in RYBP-overexpressing cells. Overexpression of RYBP reduced tumor volume and weight as well as metastatic foci in the lungs of nude mice. SRRM3 knockdown by siRNA, which is downregulated after RYBP overexpression, suppressed cell growth and metastasis in MDA-MB-231 and SK-BR-3 cells. Furthermore, qPCR analysis revealed that REST-003 ncRNA was downregulated in cells overexpressing RYBP and in SRRM3-inhibited cells. Moreover, cell invasion ability and growth were increased after SRRM3 upregulation in RYBP-overexpressing cells, but they were decreased following si-REST-003 transfection. In conclusion, overexpression of RYBP suppresses breast

Checkpoint Kinase 1 Expression Predicts Poor Prognosis in Nigerian Breast Cancer Patients.

PubMed

Ebili, Henry Okuchukwu; Iyawe, Victoria O; Adeleke, Kikelomo Rachel; Salami, Babatunde Abayomi; Banjo, Adekunbiola Aina; Nolan, Chris; Rakha, Emad; Ellis, Ian; Green, Andrew; Agboola, Ayodeji Olayinka Johnson

2018-02-01

Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population. We therefore aimed to investigate the clinicopathological, biological, and prognostic significance of CHEK1 expression in a cohort of Nigerian breast cancer cases. Tissue microarrays of 207 Nigerian breast cancer cases were tested for CHEK1 expression using immunohistochemistry. The clinicopathological, molecular, and prognostic characteristics of CHEK1-positive tumours were determined using the Chi-squared test and Kaplan-Meier and Cox regression analyses in SPSS Version 16. Nuclear expression of CHEK1 was present in 61% of breast tumours and was associated with tumour size, triple-negative cancer, basal-like phenotype, the epithelial-mesenchymal transition, p53 over-expression, DNA homologous repair pathway dysfunction, and poor prognosis. The rate expression of CHEK1 is high in Nigerian breast cancer cases and is associated with an aggressive phenotype and poor prognosis.

[Prognostic differences of phenotypes in pT1-2N0 invasive breast cancer: a large cohort study with cluster analysis].

PubMed

Wang, Z; Wang, W H; Wang, S L; Jin, J; Song, Y W; Liu, Y P; Ren, H; Fang, H; Tang, Y; Chen, B; Qi, S N; Lu, N N; Li, N; Tang, Y; Liu, X F; Yu, Z H; Li, Y X

2016-06-23

To find phenotypic subgroups of patients with pT1-2N0 invasive breast cancer by means of cluster analysis and estimate the prognosis and clinicopathological features of these subgroups. From 1999 to 2013, 4979 patients with pT1-2N0 invasive breast cancer were recruited for hierarchical clustering analysis. Age (≤40, 41-70, 70+ years), size of primary tumor, pathological type, grade of differentiation, microvascular invasion, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) were chosen as distance metric between patients. Hierarchical cluster analysis was performed using Ward's method. Cophenetic correlation coefficient (CPCC) and Spearman correlation coefficient were used to validate clustering structures. The CPCC was 0.603. The Spearman correlation coefficient was 0.617 (P<0.001), which indicated a good fit of hierarchy to the data. A twelve-cluster model seemed to best illustrate our patient cohort. Patients in cluster 5, 9 and 12 had best prognosis and were characterized by age >40 years, smaller primary tumor, lower histologic grade, positive ER and PR status, and mainly negative HER-2. Patients in the cluster 1 and 11 had the worst prognosis, The cluster 1 was characterized by a larger tumor, higher grade and negative ER and PR status, while the cluster 11 was characterized by positive microvascular invasion. Patients in other 7 clusters had a moderate prognosis, and patients in each cluster had distinctive clinicopathological features and recurrent patterns. This study identified distinctive clinicopathologic phenotypes in a large cohort of patients with pT1-2N0 breast cancer through hierarchical clustering and revealed different prognosis. This integrative model may help physicians to make more personalized decisions regarding adjuvant therapy.

Expression of BMI-1 and Mel-18 in breast tissue - a diagnostic marker in patients with breast cancer

PubMed Central

2010-01-01

Background Polycomb Group (PcG) proteins are epigenetic silencers involved in maintaining cellular identity, and their deregulation can result in cancer. Expression of Mel-18 and Bmi-1 has been studied in tumor tissue, but not in adjacent non-cancerous breast epithelium. Our study compares the expression of the two genes in normal breast epithelium of cancer patients and relates it to the level of expression in the corresponding tumors as well as in breast epithelium of healthy women. Methods A total of 79 tumors, of which 71 malignant tumors of the breast, 6 fibroadenomas, and 2 DCIS were studied and compared to the reduction mammoplastic specimens of 11 healthy women. In addition there was available adjacent cancer free tissue for 23 of the malignant tumors. The tissue samples were stored in RNAlater, RNA was isolated to create expression microarray profile. These two genes were then studied more closely first on mRNA transcription level by microarrays (Agilent 44 K) and quantitative RT-PCR (TaqMan) and then on protein expression level using immunohistochemistry. Results Bmi-1 mRNA is significantly up-regulated in adjacent normal breast tissue in breast cancer patients compared to normal breast tissue from noncancerous patients. Conversely, mRNA transcription level of Mel-18 is lower in normal breast from patients operated for breast cancer compared to breast tissue from mammoplasty. When protein expression of these two genes was evaluated, we observed that most of the epithelial cells were positive for Bmi-1 in both groups of tissue samples, although the expression intensity was stronger in normal tissue from cancer patients compared to mammoplasty tissue samples. Protein expression of Mel-18 showed inversely stronger intensity in tissue samples from mammoplasty compared to normal breast tissue from patients operated for breast cancer. Conclusion Bmi-1 mRNA level is consistently increased and Mel-18 mRNA level is consistently decreased in adjacent normal breast

Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.

2010-04-01

This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels resultmore » in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.« less

Targeting ESR1-Mutant Breast Cancer

DTIC Science & Technology

2015-09-01

Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response , including the time...CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU...Cancer W81XWH-14-1-0359 5 2. Keywords Estrogen Receptor Estrogen Response Element Metastatic Breast Cancer Ligand Binding Domain Mutation

Reduced expression of α-L-Fucosidase-1 (FUCA-1) predicts recurrence and shorter cancer specific survival in luminal B LN+ breast cancer patients.

PubMed

Bonin, Serena; Parascandolo, Alessia; Aversa, Cinzia; Barbazza, Renzo; Tsuchida, Nobuo; Castellone, Maria Domenica; Stanta, Giorgio; Vecchio, Giancarlo

2018-03-16

The lysosomal enzyme α-L-Fucosidase-1 (FUCA-1) catalyzes the hydrolytic cleavage of terminal fucose residues. FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors as its inactivation perturbs the fucosylation of proteins involved in cell adhesion, migration and metastases. Negativity to FUCA-1 was significantly related to the development of later recurrences in breast cancer patients with lymph node involvement at diagnosis. Cancer specific survival of luminal B LN+ patients was influenced by FUCA-1 expression as luminal B LN+ patients with positive expression had a longer cancer specific survival. FUCA-1 mRNA expression was inversely related to cancer stage and lymph node involvement. WB and qPCR analysis of FUCA-1 expression in breast cancer-derived cell lines confirmed an inverse relationship with tumor aggressiveness. This study shows that, within LN+ breast cancer patients, FUCA-1 is able to identify a sub-set of non recurrent patients characterized by the positive expression of FUCA-1 and that, within luminal B LN+ patients, the expression of FUCA-1 predicts longer cancer specific survival. We have analyzed FUCA-1 in 305 breast cancer patients by Immunohistochemistry (IHC), and by qPCR in breast cancer patients and in breast cancer cell lines.

Prediabetes, diabetes, and risk of breast cancer: a case-control study.

PubMed

Salinas-Martínez, Ana María; Flores-Cortés, Lillian Ivette; Cardona-Chavarría, Juan Manuel; Hernández-Gutiérrez, Brenda; Abundis, Alberto; Vázquez-Lara, Julia; González-Guajardo, Eduardo Enrique

2014-07-01

Although underlying mechanisms have been described to account for the association between prediabetes and diabetes with breast cancer, reported results have been inconsistent. We undertook this study to determine whether prediabetes and diabetes are risk factors for breast cancer in Mexican women with no family history of breast cancer in the mother, daughters, or sisters. A case-control study was carried out during 2011-2013. "Case" referred to patients with a histopathological diagnosis of breast cancer (incident and primary cases) (n = 240); "controls" were those with a BI-RADS 1 or 2 mammography result (n = 406). Categorization of prediabetes and diabetes was based on self-reporting or fasting glucose and glycated hemoglobin blood sampling results. Reproductive and sociodemographic data were collected by interview. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using multivariate unconditional binary logistic regression analysis. Prediabetes increased the risk of breast cancer in postmenopausal women (adjusted OR 2.08, 95% CI 1.10-3.96) as did diabetes (adjusted OR 2.85, 95% CI 1.55-5.26). A history of diabetes preceding breast cancer by ≥7 years and <7 years were both associated with an increased risk for breast cancer (adjusted OR 2.80, 95% CI 1.40-5.60 and 3.00, 95% CI 1.50-5.90, respectively). This is the first study in Mexico evaluating prediabetes and diabetes as breast cancer risk factors in women with no first-degree relatives with breast cancer. Our findings suggest that women with prediabetes and diabetes should be considered a more vulnerable population for early breast cancer detection. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line.

PubMed

Feng, Wen; Li, Hong-Chang; Xu, Ke; Chen, Ya-Feng; Pan, Li-Yun; Mei, Yi; Cai, Han; Jiang, Yi-Ming; Chen, Teng; Feng, Dian-Xu

2016-08-01

SHC SH2-binding protein 1, a member of Src homolog and collagen homolog (Shc) family, has been recently identified in different contexts in unbiased screening assays. It has been reported to be over-expressed in several malignant cancers. Immunohistochemistry of SHCBP1 on 128 breast cancer tissues and adjacent normal tissues were used to evaluate the prognostic significance of SHCBP1. Survival analyses were performed by Kaplan-Meier method. CRISPR/CAS9 method was used to knockout SHCBP1 expression. CRISPR/CAS9 technology was used to knockout SHCBP1 in 2 breast cancer cell lines. MTT assay, BrdU assay, colony formation assay, cell cycle assay and apoptosis analysis in MCF-7 and MDA-MB-231 cell lines were carried out to evaluate the effects of SHCBP1 on breast cancer in vitro. Immunohistochemical analysis revealed SHCBP1 was significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (82 of 128, 64%). Over-expressed SHCBP1 was correlated with advanced clinical stage and poorer survival. Ablation of SHCBP1 inhibited the proliferation in vitro. SHCBP1 knockout increased cyclin-dependent kinase inhibitor p21, and decreased the Cyclin B1 and CDK1. Our study suggests SHCBP1 is dysregulated expressed in breast cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of breast cancer. Copyright © 2016. Published by Elsevier B.V.

Breast-specific expression of MGB1/mammaglobin: an examination of 480 tumors from various organs and clinicopathological analysis of MGB1-positive breast cancers.

PubMed

Sasaki, Eiichi; Tsunoda, Nobuyuki; Hatanaka, Yutaka; Mori, Naoyoshi; Iwata, Hiroji; Yatabe, Yasushi

2007-02-01

Previously, we used the reverse transcription-polymerase chain reaction (RT-PCR) to show that mammaglobin (MGB1) can serve as a differential marker of breast cancer metastasis from primary lung cancer. However, mRNA-based methods are not appropriate for use in clinical practices. In this study, we examined MGB1 protein expression in 480 tumors from various organs using immunohistochemical detection and a tissue microarray technique. Breast cancers expressing MGB1 were also analyzed clinicopathologically to determine whether these cancers constitute a characteristic subset. Immunohistochemically, MGB1 was expressed specifically in breast cancers. Of the other cancers examined, including 29 of the head and neck, eight of the thyroid, 106 of the lung, 35 of the gastrointestinal tract, three of the pancreas, 14 of the uterine cervix and 13 of the ovary, none were positive for MGB1 except a proportion of salivary gland tumors (6/11, 55%) and endometrial cancers (3/23, 13%). Among the 238 breast cancers, MGB1 was expressed in 114 (48%), most of which were classified histologically as invasive duct or lobular carcinomas. Clinicopathologically, MGB1 expression was associated with positive expression of estrogen receptors and negative expression of CK5, but not with pathological stage, HER2 gene amplification or p53 immunoreactivity. Kaplan-Meier analysis revealed prolonged disease-free survival in patients with MGB1-positive breast cancers (log rank test, P=0.016), but the Cox proportional hazard model failed to confirm that MGB1 was an independent prognostic factor (hazard ratio 1.77, P=0.1755). In terms of practical diagnosis, MGB1 immunohistochemistry can serve as a differential marker of breast cancer metastasis from primary lung cancer for two reasons. Firstly, HER2-positive breast cancer frequently lacks estrogen receptor expression, but MGB1 is expressed in about half of this subtype. Secondly, as primary lung adenocarcinomas may express estrogen receptors, MGB1

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

PubMed Central

Trabucco, S E; Priedigkeit, N; Parachoniak, C A; Vanden Borre, P; Morley, S; Rosenzweig, M; Gay, L M; Goldberg, M E; Suh, J; Ali, S M; Ross, J; Leyland-Jones, B; Young, B; Williams, C; Park, B; Tsai, M; Haley, B; Peguero, J; Callahan, R D; Sachelarie, I; Cho, J; Atkinson, J M; Bahreini, A; Nagle, A M; Puhalla, S L; Watters, R J; Erdogan-Yildirim, Z; Cao, L; Oesterreich, S; Mathew, A; Lucas, P C; Davidson, N E; Brufsky, A M; Frampton, G M; Stephens, P J; Chmielecki, J; Lee, A V

2018-01-01

Abstract Background Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

PubMed

Hartmaier, R J; Trabucco, S E; Priedigkeit, N; Chung, J H; Parachoniak, C A; Vanden Borre, P; Morley, S; Rosenzweig, M; Gay, L M; Goldberg, M E; Suh, J; Ali, S M; Ross, J; Leyland-Jones, B; Young, B; Williams, C; Park, B; Tsai, M; Haley, B; Peguero, J; Callahan, R D; Sachelarie, I; Cho, J; Atkinson, J M; Bahreini, A; Nagle, A M; Puhalla, S L; Watters, R J; Erdogan-Yildirim, Z; Cao, L; Oesterreich, S; Mathew, A; Lucas, P C; Davidson, N E; Brufsky, A M; Frampton, G M; Stephens, P J; Chmielecki, J; Lee, A V

2018-04-01

Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Collectively, these data indicate that N-terminal ESR1

Relationship Between Mammographic Density and Breast Cancer Death in the Breast Cancer Surveillance Consortium

PubMed Central

2012-01-01

Background Women with elevated mammographic density have an increased risk of developing breast cancer. However, among women diagnosed with breast cancer, it is unclear whether higher density portends reduced survival, independent of other factors. Methods We evaluated relationships between mammographic density and risk of death from breast cancer and all causes within the US Breast Cancer Surveillance Consortium. We studied 9232 women diagnosed with primary invasive breast carcinoma during 1996–2005, with a mean follow-up of 6.6 years. Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS) density classification. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression; women with scattered fibroglandular densities (BI-RADS 2) were the referent group. All statistical tests were two-sided. Results A total of 1795 women died, of whom 889 died of breast cancer. In multivariable analyses (adjusted for site, age at and year of diagnosis, American Joint Committee on Cancer stage, body mass index, mode of detection, treatment, and income), high density (BI-RADS 4) was not related to risk of death from breast cancer (HR = 0.92, 95% CI = 0.71 to 1.19) or death from all causes (HR = 0.83, 95% CI = 0.68 to 1.02). Analyses stratified by stage and other prognostic factors yielded similar results, except for an increased risk of breast cancer death among women with low density (BI-RADS 1) who were either obese (HR = 2.02, 95% CI = 1.37 to 2.97) or had tumors of at least 2.0cm (HR = 1.55, 95% CI = 1.14 to 2.09). Conclusions High mammographic breast density was not associated with risk of death from breast cancer or death from any cause after accounting for other patient and tumor characteristics. Thus, risk factors for the development of breast cancer may not necessarily be the same as factors influencing the risk of death after breast cancer has developed. PMID:22911616

Melatonin, environmental light, and breast cancer.

PubMed

Srinivasan, V; Spence, D W; Pandi-Perumal, S R; Trakht, I; Esquifino, A I; Cardinali, D P; Maestroni, G J

2008-04-01

Although many factors have been suggested as causes for breast cancer, the increased incidence of the disease seen in women working in night shifts led to the hypothesis that the suppression of melatonin by light or melatonin deficiency plays a major role in cancer development. Studies on the 7,12-dimethylbenz[a]anthracene and N-methyl-N-nitrosourea experimental models of human breast cancer indicate that melatonin is effective in reducing cancer development. In vitro studies in MCF-7 human breast cancer cell line have shown that melatonin exerts its anticarcinogenic actions through a variety of mechanisms, and that it is most effective in estrogen receptor (ER) alpha-positive breast cancer cells. Melatonin suppresses ER gene, modulates several estrogen dependent regulatory proteins and pro-oncogenes, inhibits cell proliferation, and impairs the metastatic capacity of MCF-7 human breast cancer cells. The anticarcinogenic action on MCF-7 cells has been demonstrated at the physiological concentrations of melatonin attained at night, suggesting thereby that melatonin acts like an endogenous antiestrogen. Melatonin also decreases the formation of estrogens from androgens via aromatase inhibition. Circulating melatonin levels are abnormally low in ER-positive breast cancer patients thereby supporting the melatonin hypothesis for breast cancer in shift working women. It has been postulated that enhanced endogenous melatonin secretion is responsible for the beneficial effects of meditation as a form of psychosocial intervention that helps breast cancer patients.

Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico.

PubMed

Jaramillo-Rangel, G; Ortega-Martínez, M; Cerda-Flores, R M; Barrera-Saldaña, H A

2015-06-11

Glutathione S-transferases (GSTs) are a family of phase II metabolizing enzymes involved in carcinogen detoxification and the metabolism of various bioactive compounds. Several genes that code for these enzymes are polymorphic in an ethnicity-dependent manner, with particular genotypes previously associated with an increased risk of breast cancer. The purpose of this study was to determine the frequencies of polymorphisms in the genes GSTM1, GSTT1, GSTP1, and GSTM3 and to investigate whether an association exists between these genes and breast cancer risk in subjects from northeastern Mexico. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Gene polymorphisms were analyzed using a DNA microarray. We found an increased breast cancer risk associated with the GSTM1 gene deletion polymorphism (OR = 2.19; 95%CI = 1.50-3.21; P = 0.001). No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. The GSTM1 null genotype was associated with breast cancer risk. Our findings may be used to individualize breast cancer screening and therapeutic intervention in our population, which displays ethnic characteristics that differentiate it from other populations in Mexico.

Long non-coding RNA GHET1 promotes human breast cancer cell proliferation, invasion and migration via affecting epithelial mesenchymal transition.

PubMed

Song, Rui; Zhang, Jia; Huang, Junhua; Hai, Tao

2018-05-11

Breast cancer is a common malignancy in women and long non-coding RNAs (lncRNAs) have been shown to play key roles in the development and progression of breast cancer. In the present study, we examined the biological role of lncRNA gastric carcinoma highly expressed transcript 1 (GHET1) in breast cancer. The expression of GHET1 was determined by qRT-PCR assay; CCK-8, colony formation, Transwell invasion and migration assays detected breast cancer cell proliferation, invasion and migration; cell apoptosis and cell cycle were determined by flow cytometry; protein levels were determined by western blot assay. GHET1 was up-regulated in breast cancer tissues and cell lines, and the up-regulation of GHET1 was positively correlated with larger tumor size, advanced clinical stage, lymph node metastasis and shorter overall survival. Knockdown of GHET1 suppressed cell proliferation, invasion and migration, and induced apoptosis and G0/G1 cell cycle arrest in MCF-cells. Knockdown of GHET1 also suppressed the protein levels of N-cadherin, vimentin, and decreased the protein level of E-cadherin in MCF-7 cells. On the other hand, overexpression of GHET1 promoted cell proliferation, invasion and migration, and inhibited cell apoptosis and increased cell population at S phase in BT-20 cells. Overexpression of GHET1 also promoted epithelial mesenchymal transition (EMT) in BT-20 cells. Furthermore, knockdown of GHET1 also suppressed in vivo tumor growth of MCF-7 cells, and also decreased the protein levels of N-cadherin and vimentin, and increased the protein levels of E-cadherin in the tumor tissues from the nude mice. Our results demonstrated that GHET1 was up-regulated in breast cancer tissues and cell lines, and promoted breast cancer cell proliferation, invasion and migration by affecting EMT. Our study for the first time revealed the biological functions of GHET1 in breast cancer.

Expressive writing in early breast cancer survivors.

PubMed

Craft, Melissa A; Davis, Gail C; Paulson, René M

2013-02-01

This article is the report of a study aimed at determining whether or not expressive writing improves the quality-of-life of early breast cancer survivors. An additional aim is the investigation of whether or not the type of writing prompt makes a difference in results. The risk of distress can extend well beyond the time of a breast cancer diagnosis. Emotional expression may assist in dealing with this. Randomized controlled study. Participants (n = 120) were randomized into one of four groups: a control group (no writing) or one of three expressive writing groups: breast cancer trauma, any self-selected trauma and facts related to breast cancer. Participants wrote 20 minutes a day for 4 consecutive days. Their quality-of-life was measured, using the 'Functional Assessment of Cancer Therapy-Breast Cancer Version', at baseline and at 1 month and 6 months after writing. Paired t-tests, multivariate analysis of variance and multiple regression were used to analyse the data of the 97 participants who completed the journaling assignment and at least the first assessment, collected in 2006. Intention-to-treat analysis was used. Expressive writing about one's breast cancer, breast cancer trauma and facts related to breast cancer, significantly improved the quality-of-life outcome. Expressive writing, focusing the instructions on writing about one's living and dealing with a diagnosis of breast cancer, is recommended for early breast cancer survivors as a feasible and easily implemented treatment approach to improve quality-of-life. © 2012 Blackwell Publishing Ltd.

[Awareness of breast cancer screening among general practitioners in Mohammedia (Morocco)].

PubMed

Zine, Karima; Nani, Samira; Lahmadi, Imad Ait; Maaroufi, Abderrahmane

2016-01-01

Breast cancer is a major public health problem in Morocco. It is the most common cancer in women. Our study aims to evaluate the extent of breast cancer awareness among general practitioners (GP) in the prefecture of Mohammedia, Morocco. We conducted a cross-sectional, descriptive, exhaustive study including 97 GP working in primary health care facilities (public and private sector) of the province of Mohammedia. Participation rate was 87%. The average age of GP was 49.6 ± 8.1. Eighty percent (n = 55) of the GP misstated the incidence of breast cancer, 77.6% (n = 85) recognized the existence of a national plan to prevent and control cancer (NPPCC) in Morocco and 67.1% of GP reported the existence of a cancer registry in Morocco. General practice sector was significantly related to the awareness of NPPCC among GP and to the existence of guidelines for the early detection of breast cancer (p = 0.003 and p = 0.001 respectively). A significant relationship was found between seniority and the existence of guidelines for the early detection of breast cancer and a breast cancer registry (p = 0.005 and p = 0.002 respectively). In light of these results GP awareness and practices should be enhanced by promoting initial and continuing training on breast cancer screening.

[CHEK2-mutation in Dutch breast cancer families: expanding genetic testing for breast cancer].

PubMed

Adank, Muriel A; Hes, Frederik J; van Zelst-Stams, Wendy A G; van den Tol, M Petrousjka; Seynaeve, Caroline; Oosterwijk, Jan C

2015-01-01

In the majority of breast cancer families, DNA testing does not show BRCA1 or BRCA2 mutations and the genetic cause of breast cancer remains unexplained. Routine testing for the CHEK2*1100delC mutation has recently been introduced in breast cancer families in the Netherlands. The 1100delC mutation in the CHEK2-gene may explain the occurrence of breast cancer in about 5% of non-BRCA1/2 families in the Netherlands. In the general population the CHEK2*1100delC mutation confers a slightly increased breast cancer risk, but in a familial breast cancer setting this risk is between 35-55% for first degree female carriers. Female breast cancer patients with the CHEK2*1100delC mutation are at increased risk of contralateral breast cancer and may have a less favourable prognosis. Female heterozygous CHEK2*1100delC mutation carriers are offered annual mammography and specialist breast surveillance between the ages of 35-60 years. Prospective research in CHEK2-positive families is essential in order to develop more specific treatment and screening strategies.

PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse.

PubMed

Yang, Jing; Wu, Ning-Ni; Huang, De-Jia; Luo, Yao-Chang; Huang, Jun-Zhen; He, Hai-Yuan; Lu, Hai-Lin; Song, Wen-Ling

2017-07-01

Although the oncogenic role of PPFIA1 (liprin-α1) in breast cancer has been reported, whether its dysregulation is associated with metastasis risk or survival outcomes in breast cancer patients is not clear. Our primary data showed that PPFIA1 expression was significantly higher in liver metastatic breast tumors than in the primary tumors. Then, we tried to pool previous annotated genomic data to assess the prognostic value of PPFIA1 in distant metastasis-free survival, the risk of metastatic relapse, and metastatic relapse-free survival in breast cancer patients by data mining in two large databases, Kaplan-Meier plotter and bc-GenExMiner 4.0. Results from Kaplan-Meier plotter showed that although high PPFIA1 expression was generally associated with decreased distant metastasis-free survival in estrogen receptor+ patients, subgroup analysis only confirmed significant association in estrogen receptor+/N- (nodal negative) group (median survival, high PPFIA1 group vs low PPFIA1 cohort: 191.21 vs 236.22 months; hazard ratio: 2.23, 95% confidence interval: 1.42-3.5, p < 0.001), but not in estrogen receptor+/N+ (nodal positive) group (hazard ratio: 1.63, 95% confidence interval: 0.88-3.03, p = 0.12). In estrogen receptor- patients, there was no association between PPFIA1 expression and distant metastasis-free survival, no matter in Nm (nodal status mixed), N-, or N+ subgroups. In bc-GenExMiner 4.0, Nottingham Prognostic Index- and Adjuvant! Online-adjusted analysis validated the independent prognostic value of PPFIA1 in metastatic risks in estrogen receptor+/N- patients. Based on these findings, we infer that high PPFIA1 expression might be an independent prognostic indicator of increased metastatic relapse risk in patients with estrogen receptor+/N- breast cancer, but not in estrogen receptor+/N+ or estrogen receptor- patients.

Reduced Mortality With Partial-Breast Irradiation for Early Breast Cancer: A Meta-Analysis of Randomized Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaidya, Jayant S., E-mail: jayant.vaidya@ucl.ac.uk; Department of Surgery, Royal Free Hospital, London; Department of Surgery, Whittington Health, London

Purpose: With earlier detection and more effective treatment, mortality from breast cancer continues to fall and it has become increasingly important to reduce the toxicity of treatments. Partial-breast radiation therapy, which focuses radiation to the tumor bed, may achieve this aim. We analyzed mortality differences in randomized trials of partial-breast irradiation (PBI). Methods and Materials: We included data from published randomized trials of PBI (alone or as part of a risk-adapted approach) versus whole-breast irradiation (WBI) for invasive breast cancer suitable for breast-conserving therapy. We identified trials using PubMed and Google searches with the terms “partial breast irradiation” OR “intraoperativemore » radiotherapy” OR “IMRT” OR (“accelerated” AND “radiation”) AND “randomised/randomized,” as well as through discussion with colleagues in the field. We calculated the proportion of patients who had events in each randomized arm at 5 years' follow-up and created a forest plot using Stata, version 14.1. Results: We identified 9 randomized trials of PBI versus WBI in invasive breast cancer; 5-year outcomes were available for non–breast cancer mortality in 5 trials (n=4489) and for breast cancer mortality in 4 trials (n=4231). The overall mortality was 4.9%. There was no detectable heterogeneity between the trials for any of the outcomes. There was no difference in the proportion of patients dying of breast cancer (difference, 0.000% [95% confidence interval (CI), −0.7 to +0.7]; P=.999). Non–breast cancer mortality with PBI was lower than with WBI (difference, 1.1% [95% CI, −2.1% to −0.2%]; P=.023). Total mortality with PBI was also lower than with WBI (difference, 1.3% [95% CI, −2.5% to 0.0%]; P=.05). Conclusions: Use of PBI instead of WBI in selected patients results in a lower 5-year non–breast cancer and overall mortality, amounting to a 25% reduction in relative terms. This information should be included

Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer

PubMed Central

Torres-Mejía, Gabriela; Royer, Robert; Llacuachaqui, Marcia; Akbari, Mohammad R.; Giuliano, Anna R.; Martínez-Matsushita, Louis; Angeles-Llerenas, Angélica; Ortega-Olvera, Carolina; Ziv, Elad; Lazcano-Ponce, Eduardo; Phelan, Catherine M.; Narod, Steven A.

2015-01-01

Background Germline mutations in the BRCA1 and BRCA2 genes confer an estimated 58–80% lifetime risk of breast cancer. In general, screening is done for cancer patients if a relative has been diagnosed with breast or ovarian cancer. There are few data on the prevalence of mutations in these genes in Mexican women with breast cancer and this hampers efforts to develop screening policies in Mexico. Methods We screened 810 unselected women with breast cancer from three cities in Mexico (Mexico City, Veracruz and Monterrey) for mutations in BRCA1 and BRCA2, including a panel of 26 previously reported mutations. Results Thirty-five mutations were identified in 34 women (4.3% of total) including 20 BRCA1 mutations and 15 BRCA2 mutations. Twenty-two of the 35 mutations were recurrent mutations (62.8%). Only five of the 34 mutation carriers had a first-degree relative with breast cancer (three with BRCA1 and two with BRCA2 mutations). Conclusion These results support the rationale for a strategy of screening for recurrent mutations in all women with breast cancer in Mexico, as opposed to restricting screening to those with a sister or mother with breast or ovarian cancer. Impact These results will impact cancer genetic testing in Mexico and the identification of at-risk individuals who will benefit from increased surveillance. PMID:25371446

Family history of breast or ovarian cancer modifies the risk of secondary leukemia after breast cancer: results from a population-based study.

PubMed

Verkooijen, Helena M; Fioretta, Gerald; Rapiti, Elisabetta; Vlastos, Georges; Neyroud-Caspar, Isabelle; Chappuis, Pierre O; Bouchardy, Christine

2008-03-01

We evaluated the impact of a family history of breast/ovarian cancer on the risk of secondary leukemia following breast cancer. At the Geneva cancer registry, we identified 4,397 patients diagnosed with invasive breast cancer between 1990 and 2004. Patients were followed up for leukemia until the end of 2005. Family history was categorized as positive in patients with >or=1 first- or second-degree relative with breast/ovarian cancer. We compared leukemia rates in patients with positive and negative family histories with those expected in the general population, generating standardized incidence ratios (SIRs). With Cox regression analysis, we calculated adjusted risks of secondary leukemia in patients with familial risks compared to those without it. Breast cancer patients had a significantly increased risk of secondary acute leukemia (SIR 3.2, 95% CI: 1.2-6.9) but not of chronic leukemia (SIR 1.6, 95% CI: 0.6-3.5). Among patients with a positive family history (n = 1.125, 25.6%), the SIRs were 5.7 (95% CI: 1.2-16.6) for acute and 5.2 (95% CI: 1.4-13.3) for chronic leukemia. Among breast cancer patients, family history was independently associated with leukemia [adjusted hazard ratio (HR(adj)) of 3.2, 95% CI: 1.1-9.2, among patient with vs. without family history]. The effect of family history was stronger for chronic leukemia (HR(adj): 11.6, 95% CI 1.3-104.7) than for acute leukemia (HR(adj) 1.6, 95% CI: 0.4-6.6). Breast cancer patients with a family history of breast/ovarian have an increased risk of secondary leukemia, both compared to the general population as well as to breast cancer patients without family histories. This excess risk is largely due to the increased risk of secondary chronic leukemia. (c) 2007 Wiley-Liss, Inc.

UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer.

PubMed

Ning, Kuan; Wang, Teng; Sun, Xu; Zhang, Pengfei; Chen, Yun; Jin, Jian; Hua, Dong

2017-06-01

Chemotherapy resistance has become a serious challenge in the treatment of breast cancer. Previous studies showed cells can transfer proteins, including those responsible for drug resistance to adjacent cells via exosomes. The switches of drug resistance via exosomes transfer were assessed by CellTiter-Blue Viability assay, flow cytometry, and immunostaining analysis. Relative protein levels of Ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1), P-glycoprotein (P-gp), extracellular-signal regulated protein kinase1/2 (ERK1/2), and phospho-extracellular-signal regulated protein kinase1/2 (p-ERK1/2) were measured by Western blot. Immunohistochemistry was performed on 93 breast cancer samples to assess the associations of UCH-L1 levels with immunofluorescence value of UCH-L1 in circulating exosomes. The Adriamycin-resistant human breast cancer cells (MCF7/ADM) secreted exosomes carrying UCH-L1 and P-gp proteins into the extracellular microenvironment then integrated into Adriamycin-sensitive human breast cancer cells (MCF7/WT) in a time-dependent manner, transferring the chemoresistance phenotype. Notably, in blood samples from patients with breast cancer, the level of exosomes carrying UCH-L1 before chemotherapy was significantly negatively correlated with prognosis. Our study demonstrated that UCH-L1-containing exosomes can transfer chemoresistance to recipient cells and these exosomes may be useful as non-invasive diagnostic biomarkers for detection of chemoresitance in breast cancer patients, achieving more effective and individualized chemotherapy. © 2017 Wiley Periodicals, Inc.

Estrogen/Progesterone Receptor Negativity and HER2 Positivity Predict Locoregional Recurrence in Patients With T1a,bN0 Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, Jeffrey M.; Gonzalez-Angulo, Ana M.; Guray, Merih

2010-08-01

Purpose: Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors {<=}1 cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab. Methods and Materials: The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed.more » We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study. Results: With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy (p = .347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p = .016), PR-negative (9.0% vs. 4.2%, p = .009), or HER2-positive (17.5% vs. 3.9%, p = 0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p = .046) and HER2-positive disease (hazard ratio, 3.13, p = .016) independently predicted for LRR. Conclusion: Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.« less

Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer

PubMed Central

Hue, Trisha F.; Cummings, Steven R.; Cauley, Jane A.; Bauer, Douglas C.; Ensrud, Kristine E.; Barrett-Connor, Elizabeth; Black, Dennis M.

2015-01-01

IMPORTANCE Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. OBJECTIVE To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. DESIGN, SETTING, AND PARTICIPANTS The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. INTERVENTION Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). MAIN OUTCOMES AND MEASURES Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. RESULTS There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84–1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the

Observed and Predicted Risk of Breast Cancer Death in Randomized Trials on Breast Cancer Screening

PubMed Central

Autier, Philippe; Sullivan, Richard; Boyle, Peter

2016-01-01

Background The role of breast screening in breast cancer mortality declines is debated. Screening impacts cancer mortality through decreasing the number of advanced cancers with poor diagnosis, while cancer treatment works through decreasing the case-fatality rate. Hence, reductions in cancer death rates thanks to screening should directly reflect reductions in advanced cancer rates. We verified whether in breast screening trials, the observed reductions in the risk of breast cancer death could be predicted from reductions of advanced breast cancer rates. Patients and Methods The Greater New York Health Insurance Plan trial (HIP) is the only breast screening trial that reported stage-specific cancer fatality for the screening and for the control group separately. The Swedish Two-County trial (TCT)) reported size-specific fatalities for cancer patients in both screening and control groups. We computed predicted numbers of breast cancer deaths, from which we calculated predicted relative risks (RR) and (95% confidence intervals). The Age trial in England performed its own calculations of predicted relative risk. Results The observed and predicted RR of breast cancer death were 0.72 (0.56–0.94) and 0.98 (0.77–1.24) in the HIP trial, and 0.79 (0.78–1.01) and 0.90 (0.80–1.01) in the Age trial. In the TCT, the observed RR was 0.73 (0.62–0.87), while the predicted RR was 0.89 (0.75–1.05) if overdiagnosis was assumed to be negligible and 0.83 (0.70–0.97) if extra cancers were excluded. Conclusions In breast screening trials, factors other than screening have contributed to reductions in the risk of breast cancer death most probably by reducing the fatality of advanced cancers in screening groups. These factors were the better management of breast cancer patients and the underreporting of breast cancer as the underlying cause of death. Breast screening trials should publish stage-specific fatalities observed in each group. PMID:27100174

Observed and Predicted Risk of Breast Cancer Death in Randomized Trials on Breast Cancer Screening.

PubMed

Autier, Philippe; Boniol, Mathieu; Smans, Michel; Sullivan, Richard; Boyle, Peter

2016-01-01

The role of breast screening in breast cancer mortality declines is debated. Screening impacts cancer mortality through decreasing the number of advanced cancers with poor diagnosis, while cancer treatment works through decreasing the case-fatality rate. Hence, reductions in cancer death rates thanks to screening should directly reflect reductions in advanced cancer rates. We verified whether in breast screening trials, the observed reductions in the risk of breast cancer death could be predicted from reductions of advanced breast cancer rates. The Greater New York Health Insurance Plan trial (HIP) is the only breast screening trial that reported stage-specific cancer fatality for the screening and for the control group separately. The Swedish Two-County trial (TCT)) reported size-specific fatalities for cancer patients in both screening and control groups. We computed predicted numbers of breast cancer deaths, from which we calculated predicted relative risks (RR) and (95% confidence intervals). The Age trial in England performed its own calculations of predicted relative risk. The observed and predicted RR of breast cancer death were 0.72 (0.56-0.94) and 0.98 (0.77-1.24) in the HIP trial, and 0.79 (0.78-1.01) and 0.90 (0.80-1.01) in the Age trial. In the TCT, the observed RR was 0.73 (0.62-0.87), while the predicted RR was 0.89 (0.75-1.05) if overdiagnosis was assumed to be negligible and 0.83 (0.70-0.97) if extra cancers were excluded. In breast screening trials, factors other than screening have contributed to reductions in the risk of breast cancer death most probably by reducing the fatality of advanced cancers in screening groups. These factors were the better management of breast cancer patients and the underreporting of breast cancer as the underlying cause of death. Breast screening trials should publish stage-specific fatalities observed in each group.

Interactions of Family History of Breast Cancer with Radiotherapy in Relation to the Risk of Breast Cancer Recurrence.

PubMed

Li, Danmeng; Mai, Volker; Gerke, Travis; Pinney, Susan Mengel; Yaghjyan, Lusine

2017-12-01

We examined associations between a family history of breast cancer and the risk of breast cancer recurrence in women who received or did not receive radiotherapy. Our study included 2,440 women enrolled in the Breast Cancer Registry of Greater Cincinnati. Information on breast cancer risk factors, including detailed family history of breast cancer, characteristics of the primary tumor, treatment received, and recurrence status was collected at baseline and via updates. Associations between a family history of breast cancer and the risk of breast cancer recurrence were examined separately in women treated with and without radiotherapy using survival analysis. Over an average follow-up time of 8.78 years, we found no associations between a family history of breast cancer and the risk of breast cancer recurrence among women with a history of radiotherapy (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.75-1.23). Among women who did not receive radiotherapy, the total number of relatives with breast cancer was positively associated with the risk of breast cancer recurrence (HR, 1.21; 95% CI, 1.00-1.47). We found no interactions of radiotherapy with family history (p-interaction >0.05). Radiotherapy for a primary breast cancer in women with a family history of breast cancer does not increase risk of breast cancer recurrence. If these findings are replicated in future studies, the results may translate into an important health message for breast cancer survivors with a family history of breast cancer.

Breast cancer risk associations with birth order and maternal age according to breast-feeding status in infancy

PubMed Central

Nichols, Hazel B.; Trentham-Dietz, Amy; Sprague, Brian L.; Hampton, John M.; Titus-Ernstoff, Linda; Newcomb, Polly A.

2009-01-01

Background Early life risk factors for breast cancer have been investigated in relation to hormonal, nutritional, infectious, and/or genetic hypotheses. Recently, studies of potential health effects associated with exposure to environmental contaminants in breastmilk have been considered. Methods We analyzed data from a population-based case-control study of female Wisconsin residents. Cases (N=2,016) had an incident diagnosis of invasive breast cancer in 2002−2006 reported to the statewide tumor registry. Controls (N=1,960) of similar ages were randomly selected from driver's license lists. Risk factor information was collected during structured telephone interviews. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated from multivariable logistic regression. Results In multivariable models, maternal age and birth order were not associated with breast cancer risk in the full study population. The odds ratio for breast cancer risk associated with having been breastfed in infancy was 0.83 (95% CI 0.72−0.96). In analyses restricted to breastfed women, maternal age associations with breast cancer were null (p-value=0.2). Increasing maternal age was negatively associated with breast cancer risk among women who were not breastfed; the odds ratio for breast cancer associated with each 5-year increase in maternal age was 0.90 (95% CI 0.82−1.00). Higher birth order was inversely associated with breast cancer risk among breastfed women (OR=0.58; 95% CI 0.39−0.86 for women with ≥3 older siblings compared to first-born women) but not among non-breastfed women (OR=1.13; 95% CI 0.81−1.57). Conclusion These findings suggest that early life risk factor associations for breast cancer may differ according to breastfeeding status in infancy. PMID:18379425

Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization.

PubMed

Driffort, Virginie; Gillet, Ludovic; Bon, Emeline; Marionneau-Lambot, Séverine; Oullier, Thibauld; Joulin, Virginie; Collin, Christine; Pagès, Jean-Christophe; Jourdan, Marie-Lise; Chevalier, Stéphan; Bougnoux, Philippe; Le Guennec, Jean-Yves; Besson, Pierre; Roger, Sébastien

2014-12-11

Na(V)1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, Na(V)1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. In this study, we showed that the extinction of Na(V)1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited Na(V)1.5 currents in breast cancer cells and reduced Na(V)1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by Na(V)1.5-expressing human breast cancer cells. Taken together, our results demonstrate the importance of Na(V)1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Na(V) activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.

Identifying Breast Cancer Oncogenes

DTIC Science & Technology

2010-10-01

08-1-0767 TITLE: Identifying Breast Cancer Oncogenes PRINCIPAL INVESTIGATOR: Yashaswi Shrestha... Breast Cancer Oncogenes 5a. CONTRACT NUMBER W81XWH-08-1-0767 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Yashaswi...SUPPLEMENTARY NOTES 14. ABSTRACT Breast cancer is attributed to genetic alterations, the majority of which are yet to be characterized. Oncogenic

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

PubMed

Couch, Fergus J; Hart, Steven N; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E; Godwin, Andrew K; Pankratz, V Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I; Beckmann, Matthias W; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B; Slamon, Dennis J; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M; Tapper, William J; Durcan, Lorraine; Cross, Simon S; Pilarski, Robert; Shapiro, Charles L; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L; Vachon, Celine M; Eccles, Diana M; Fasching, Peter A

2015-02-01

Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. © 2014 by American Society of Clinical Oncology.

Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer

PubMed Central

Couch, Fergus J.; Hart, Steven N.; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E.; Godwin, Andrew K.; Pankratz, V. Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I.; Beckmann, Matthias W.; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B.; Slamon, Dennis J.; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M.; Tapper, William J.; Durcan, Lorraine; Cross, Simon S.; Pilarski, Robert; Shapiro, Charles L.; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L.; Vachon, Celine M.; Eccles, Diana M.; Fasching, Peter A.

2015-01-01

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. PMID:25452441

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.

PubMed

Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Neuhausen, Susan L; Ding, Yuan Chun; Rebbeck, Timothy R; Weitzel, Jeffrey N; Lynch, Henry T; Isaacs, Claudine; Ganz, Patricia A; Tomlinson, Gail; Olopade, Olufunmilayo I; Couch, Fergus J; Wang, Xianshu; Lindor, Noralane M; Pankratz, Vernon S; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Birk Jensen, Uffe; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E J; Blok, Marinus J; Aalfs, Cora M; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J; Porteous, Mary E; Walker, Lisa; Kennedy, M John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V O; Jønson, Lars; Agnarsson, Bjarni A; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Schwartz, Peter E; Blank, Stephanie V; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F

2010-12-01

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Male Breast Cancer Has Limited Effect on Survivor's Perceptions of Their Own Masculinity.

PubMed

Rayne, Sarah; Schnippel, Kathryn; Thomson, John; Reid, Joanna; Benn, Carol

2017-03-01

The purpose of the current study was to describe male breast cancer in Johannesburg, South Africa, and assess whether male breast cancer patients' perception of their own masculinity was affected by having a cancer commonly seen in women. A retrospective file review was carried out at two hospitals, one private and one government, of male breast cancer patients from 2007 to 2012 followed by a telephone survey of patients identified during review. Of approximately 3,000 breast cancer patients seen in the 5 years reviewed, 23 cases of male breast cancer were identified. Most were diagnosed with invasive ductal carcinoma ( n = 19, 83%). Stage at presentation was from stages 0 to 3 (Stage 0 [ n = 2, 9%], Stage 1 [ n = 3, 13%], Stage 2 [ n = 12, 52%], Stage 3 [ n = 6, 26%]) and no patients were metastatic at presentation. The telephonic survey was completed by 18 patients (78%). Nearly all ( n = 17/18) shared their diagnosis with family and close friends. Two thirds of patients delayed presentation and government hospital patients were more likely to present later than private sector hospital patients. Although most male breast cancer patients sampled did not perceive the breast cancer diagnosis as affecting their masculinity, Black men and those treated in government hospitals were less likely to be aware of male breast cancer, and were more likely to have their perception of their own masculinity affected.

Role of Polyamine Oxidase (PAOh1/SMO) in Human Breast Cancer

DTIC Science & Technology

2007-04-01

polyamine spermidine , 3-aminopropanal, and the reactive oxygen species, H2O2. Previous work by our research group has shown that SMO can be induced by...spermine/ spermidine N1-acetyltransferase (SSAT). Treatment of MCF-10a cells with CSE resulted in a rapid 3-fold induction of SSAT mRNA at the one hour time...and spermine/ spermidine N1 acetyl- transferase (SSAT, open bars) in MCF- 10a human breast cancer cells by cigarette smoke extract (CSE) at the

Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tiang, Jacky M.; Butcher, Neville J., E-mail: n.butcher@uq.edu.au; Minchin, Rodney F.

2010-02-26

Arylamine N-acetyltransferase 1 is a phase II metabolizing enzyme that has been associated with certain breast cancer subtypes. While it has been linked to breast cancer risk because of its role in the metabolic activation and detoxification of carcinogens, recent studies have suggested it may be important in cell growth and survival. To address the possible importance of NAT1 in breast cancer, we have used a novel small molecule inhibitor (Rhod-o-hp) of the enzyme to examine growth and invasion of the breast adenocarcinoma line MDA-MB-231. The inhibitor significantly reduced cell growth by increasing the percent of cells in G2/M phasemore » of the cell cycle. Rhod-o-hp also reduced the ability of the MDA-MB-231 cells to grow in soft agar. Using an in vitro invasion assay, the inhibitor significantly reduced the invasiveness of the cells. To test whether this effect was due to inhibition of NAT1, the enzyme was knocked down using a lentivirus-based shRNA approach and invasion potential was significantly reduced. Taken together, the results of this study demonstrate that NAT1 activity may be important in breast cancer growth and metastasis. The study suggests that NAT1 is a novel target for breast cancer treatment.« less

Development of Tyrosine-Based Radiotracer 99mTc-N4-Tyrosine for Breast Cancer Imaging

PubMed Central

Kong, Fan-Lin; Ali, Mohammad S.; Rollo, Alex; Smith, Daniel L.; Zhang, Yinhan; Yu, Dong-Fang; Yang, David J.

2012-01-01

The purpose of this study was to develop an efficient way to synthesize 99mTc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-tyrosine (99mTc-N4-Tyrosine), a novel amino acid-based radiotracer, and evaluate its potential in breast cancer gamma imaging. Precursor N4-Tyrosine was synthesized using a 5-step procedure, and its total synthesis yield was 38%. It was successfully labeled with 99mTc with high radiochemical purity (>95%). Cellular uptake of 99mTc-N4-Tyrosine was much higher than that of 99mTc-N4 and the clinical gold standard 18F-2-deoxy-2-fluoro-glucose (18F-FDG) in rat breast tumor cells in vitro. Tissue uptake and dosimetry estimation in normal rats revealed that 99mTc-N4-Tyrosine could be safely administered to humans. Evaluation in breast tumor-bearing rats showed that although 99mTc-N4-Tyrosine appeared to be inferior to 18F-FDG in distinguishing breast tumor tissue from chemical-induced inflammatory tissue, it had high tumor-to-muscle uptake ratios and could detect breast tumors clearly by planar scintigraphic imaging. 99mTc-N4-Tyrosine could thus be a useful radiotracer for use in breast tumor diagnostic imaging. PMID:22496612

XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

PubMed

Chen, Xi; Iliopoulos, Dimitrios; Zhang, Qing; Tang, Qianzi; Greenblatt, Matthew B; Hatziapostolou, Maria; Lim, Elgene; Tam, Wai Leong; Ni, Min; Chen, Yiwen; Mai, Junhua; Shen, Haifa; Hu, Dorothy Z; Adoro, Stanley; Hu, Bella; Song, Minkyung; Tan, Chen; Landis, Melissa D; Ferrari, Mauro; Shin, Sandra J; Brown, Myles; Chang, Jenny C; Liu, X Shirley; Glimcher, Laurie H

2014-04-03

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.

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

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.

RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients.

PubMed

Fan, Cong; Zhang, Juan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

2018-05-04

RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In this study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n=6 cases; K994fs, n=5 cases; and H1269fs, n=5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5000 healthy controls was 0.18% (9/5000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; P = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; P=0.018] and disease-specific survival (DSS) (adjusted HR 4.36; 95% CI, 1.58-12.03; P=0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared with patients without these mutations. This article is protected by copyright. All rights reserved. © 2018 UICC.

Sirtuin 1-dependent resveratrol cytotoxicity and pro-differentiation activity on breast cancer cells.

PubMed

Deus, Cláudia M; Serafim, Teresa L; Magalhães-Novais, Silvia; Vilaça, Andreia; Moreira, Ana C; Sardão, Vilma A; Cardoso, Susana M; Oliveira, Paulo J

2017-03-01

Sirtuins regulate several processes associated with tumor development. Resveratrol was shown to stimulate sirtuin 1 and 3 (SIRT1/3) activities and to result in cytotoxicity for some tumor types. The relationship between modulation of sirtuin activities, cellular metabolic remodeling and resveratrol cytotoxicity mechanism on breast cancer cells is still an open question. Here, we evaluated whether sirtuin 1 and 3 are involved in resveratrol toxicity and whether resveratrol leads to a metabolic remodeling and cell differentiation. Results using the Extracellular Flux Analyzer indicated that resveratrol inhibits mitochondrial respiration in breast cancer cells. We also demonstrated here for the first time that resveratrol cytotoxic effects on breast cancer cells were modulated by SIRT1 and also involved mitochondrial complex I inhibition. Importantly, we also demonstrated that resveratrol reduced the pool of breast cancer cells with stemness markers through a SIRT1-dependent mechanism. Our data highlights the role of SIRT1 in regulating resveratrol induced differentiation and/or toxicity in breast cancer cells.

Cyclin D1 and Cyclin E as Markers of Therapeutic Responsiveness in Breast Cancer

DTIC Science & Technology

2002-05-01

address whether cyclin D1 and cyclin E were predictive markers for therapeutic responsiveness in breast cancer. Both estrogen and progesterone ...although whether progesterone is tion of p 18 N K4c and increased association of the CDK stimulatory or inhibitory for normal breast epithelium remains...steroid progesterone and its synthetic ana- p2 7Ki pl and p21 ip 1 available to bind other proteins (8). Thus, logues, progestins, have complex effects

Statin Use and Breast Cancer Risk in the Nurses' Health Study.

PubMed

Borgquist, Signe; Tamimi, Rulla M; Chen, Wendy Y; Garber, Judy E; Eliassen, A Heather; Ahern, Thomas P

2016-01-01

Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82-1.1; current users: HRadj, 1.1; 95% CI, 0.92-1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. ©2016 American Association for Cancer Research.

Statin use and breast cancer risk in the Nurses’ Health Study

PubMed Central

Borgquist, Signe; Tamimi, Rulla M.; Chen, Wendy Y.; Garber, Judy E.; Eliassen, A. Heather; Ahern, Thomas P.

2016-01-01

Pre-clinical studies support an anti-cancer effect of statin drugs, yet epidemiological evidence remains inconsistent regarding their role in breast cancer primary prevention. Here we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses’ Health Study cohort. Post-menopausal Nurses’ Health Study participants without a cancer history were followed from 2000 until 2012 (n=79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence (former users: HRadj=0.96, 95% CI: 0.82, 1.1; current users: HRadj=1.1, 95% CI: 0.92, 1.3). Associations did not differ by estrogen receptor status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histological subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. PMID:26762806

Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

PubMed Central

Antoniou, Antonis C.; McGuffog, Lesley; Humphreys, Manjeet K.; Dunning, Alison M.; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Dork, Thilo; Schürmann, Peter; Karstens, Johann H.; Hillemanns, Peter; Couch, Fergus J.; Olson, Janet; Vachon, Celine; Wang, Xianshu; Cox, Angela; Brock, Ian; Elliott, Graeme; Reed, Malcolm W.R.; Burwinkel, Barbara; Meindl, Alfons; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Broeks, Annegien; Schmidt, Marjanka K.; Van ‘t Veer, Laura J.; Braaf, Linde M.; Johnson, Nichola; Fletcher, Olivia; Gibson, Lorna; Peto, Julian; Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Rahman, Nazneen; Wu, Pei-Ei; Yu, Jyh-Cherng; Hsiung, Chia-Ni; Shen, Chen-Yang; Southey, Melissa C.; Hopper, John L.; Hammet, Fleur; Van Dorpe, Thijs; Dieudonne, Anne-Sophie; Hatse, Sigrid; Lambrechts, Diether; Andrulis, Irene L.; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Juri I.; Prokofieva, Daria; Bermisheva, Marina; Khusnutdinova, Elza; van Asperen, Christi J.; Tollenaar, Robert A.E.M.; Hooning, Maartje J.; Devilee, Peter; Margolin, Sara; Lindblom, Annika; Milne, Roger L.; Arias, José Ignacio; Zamora, M. Pilar; Benítez, Javier; Severi, Gianluca; Baglietto, Laura; Giles, Graham G.; kConFab; Group, AOCS Study; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Holland, Helene; Healey, Sue; Wang-Gohrke, Shan; Chang-Claude, Jenny; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Agnarsson, Bjarni A.; Caligo, Maria A.; Godwin, Andrew K.; Nevanlinna, Heli; Heikkinen, Tuomas; Fredericksen, Zachary; Lindor, Noralane; Nathanson, Katherine L.; Domchek, Susan M.; SWE-BRCA; Loman, Niklas; Karlsson, Per; Askmalm, Marie Stenmark; Melin, Beatrice; von Wachenfeldt, Anna; HEBON; Hogervorst, Frans B. L.; Verheus, Martijn; Rookus, Matti A.; Seynaeve, Caroline; Oldenburg, Rogier A.; Ligtenberg, Marjolijn J.; Ausems, Margreet G.E.M.; Aalfs, Cora M.; Gille, Hans J.P.; Wijnen, Juul T.; Gómez García, Encarna B.; EMBRACE; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Luccarini, Craig; Pichert, Gabriella; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Ong, Kai-Ren; Cook, Jackie; Douglas, Fiona; Hodgson, Shirley; Evans, D. Gareth; Eeles, Rosalind; Gold, Bert; Pharoah, Paul D.P.; Offit, Kenneth; Chenevix-Trench, Georgia; Easton, Douglas F.

2012-01-01

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80–1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk. PMID:22768030

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

PubMed

Kirchhoff, Tomas; Gaudet, Mia M; Antoniou, Antonis C; McGuffog, Lesley; Humphreys, Manjeet K; Dunning, Alison M; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Dork, Thilo; Schürmann, Peter; Karstens, Johann H; Hillemanns, Peter; Couch, Fergus J; Olson, Janet; Vachon, Celine; Wang, Xianshu; Cox, Angela; Brock, Ian; Elliott, Graeme; Reed, Malcolm W R; Burwinkel, Barbara; Meindl, Alfons; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Broeks, Annegien; Schmidt, Marjanka K; Van 't Veer, Laura J; Braaf, Linde M; Johnson, Nichola; Fletcher, Olivia; Gibson, Lorna; Peto, Julian; Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Rahman, Nazneen; Wu, Pei-Ei; Yu, Jyh-Cherng; Hsiung, Chia-Ni; Shen, Chen-Yang; Southey, Melissa C; Hopper, John L; Hammet, Fleur; Van Dorpe, Thijs; Dieudonne, Anne-Sophie; Hatse, Sigrid; Lambrechts, Diether; Andrulis, Irene L; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Juri I; Prokofieva, Daria; Bermisheva, Marina; Khusnutdinova, Elza; van Asperen, Christi J; Tollenaar, Robert A E M; Hooning, Maartje J; Devilee, Peter; Margolin, Sara; Lindblom, Annika; Milne, Roger L; Arias, José Ignacio; Zamora, M Pilar; Benítez, Javier; Severi, Gianluca; Baglietto, Laura; Giles, Graham G; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Holland, Helene; Healey, Sue; Wang-Gohrke, Shan; Chang-Claude, Jenny; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Agnarsson, Bjarni A; Caligo, Maria A; Godwin, Andrew K; Nevanlinna, Heli; Heikkinen, Tuomas; Fredericksen, Zachary; Lindor, Noralane; Nathanson, Katherine L; Domchek, Susan M; Loman, Niklas; Karlsson, Per; Stenmark Askmalm, Marie; Melin, Beatrice; von Wachenfeldt, Anna; Hogervorst, Frans B L; Verheus, Martijn; Rookus, Matti A; Seynaeve, Caroline; Oldenburg, Rogier A; Ligtenberg, Marjolijn J; Ausems, Margreet G E M; Aalfs, Cora M; Gille, Hans J P; Wijnen, Juul T; Gómez García, Encarna B; Peock, Susan; Cook, Margaret; Oliver, Clare T; Frost, Debra; Luccarini, Craig; Pichert, Gabriella; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Ong, Kai-Ren; Cook, Jackie; Douglas, Fiona; Hodgson, Shirley; Evans, D Gareth; Eeles, Rosalind; Gold, Bert; Pharoah, Paul D P; Offit, Kenneth; Chenevix-Trench, Georgia; Easton, Douglas F

2012-01-01

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis.

PubMed

Wen, Wanqing; Cai, Qiuyin; Shu, Xiao-Ou; Cheng, Jia-Rong; Parl, Fritz; Pierce, Larry; Gao, Yu-Tang; Zheng, Wei

2005-02-01

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.

Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer.

PubMed

Dawood, Shaheenah; Rugo, Hope S

2016-12-01

This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. A fifth phase Ib trial reported a 38% response rate in metastatic triple negative breast cancer treated with the combination of a PD-L1 inhibitor and nab-paclitaxel chemotherapy. Treatment is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. Immune checkpoint inhibitor therapy has recently been shown to have clinical efficacy in the treatment of breast cancer. The most compelling data are in the triple negative subtype, with responses documented in hormone receptor positive disease as well. Numerous trials are evaluating various combination strategies and biomarkers in early and late stage disease to enhance immunogenicity and response.

[Efficacy and safety of TS-1 monotherapy for advanced/metastatic breast cancer - an observational study by the Kumamoto Breast Cancer Cooperative Group(KBCCG)].

PubMed

Yamamoto, Yutaka; Nishimura, Reiki; Tanigawa, Tomio; Kawano, Ichiro; Hayashi, Kyoji; Kuramoto, Masafumi; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka

2014-10-01

TS-1, an oral fluoropyrimidine, is known to be effective for the treatment of various carcinomas including advanced/metastatic breast cancer.The Kumamoto Breast Cancer Cooperative Group(KBCCG)conducted an observational study, wherein, the efficacy and safety of TS-1 monotherapy was analyzed in 35 patients with recurrent or metastatic breast cancer.The median time to cancer progression was 3.7 months, overall response rate was 12%, and clinical benefit rate was 32%. Adverse events were observed in 27 patients(77%), and adverse events of Grade >3 were observed in 7 patients(20%). The rate of treatment-related Grade 3 and 4 adverse events increased, and was associated with poor levels of creatinine clearance(Ccr)ie <60mL/min.This study suggests that TS-1 monotherapy can potentially be used as a salvage treatment for advanced/metastatic breast cancer owing to its safety and efficacy.Measuring the level of Ccr before TS-1 therapy should be considered to avoid severe adverse events.

A Targeted RNAi Screen of the Breast Cancer Genome Identifies KIF14 and TLN1 as Genes That Modulate Docetaxel Chemosensitivity in Triple-Negative Breast Cancer

PubMed Central

Singel, Stina Mui; Cornelius, Crystal; Batten, Kimberly; Fasciani, Gail; Wright, Woodring E.; Lum, Lawrence; Shay, Jerry W.

2015-01-01

Purpose To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer. Experimental Design We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor–negative, progesterone receptor–negative, and Her2-negative (ER−, PR−, and Her2−, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model. Results From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor–positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays. Conclusion KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC. PMID:23479679

Breast conservation in the setting of contemporary multimodality treatment provides excellent outcomes for patients with occult primary breast cancer.

PubMed

Rueth, Natasha M; Black, Dalliah M; Limmer, Angela R; Gabriel, Emmanuel; Huo, Lei; Fornage, Bruno D; Dogan, Basak E; Chavez-MacGregor, Mariana; Yi, Min; Hunt, Kelly K; Strom, Eric A

2015-01-01

To evaluate recurrence and survival for patients with occult (T0N+) breast cancer who underwent contemporary treatment, assessing outcomes for breast conservation and mastectomy. We performed a single-institution review of women with occult breast cancer presenting with axillary metastasis without identifiable breast tumor or distant metastasis. We excluded patients with tumors in the axillary tail or mastectomy specimen, patients with additional nonbreast cancer diagnoses, and patients with a history of breast cancer. Breast conservation was defined as axillary node dissection with radiation therapy, without breast surgery. We evaluated patient, tumor, treatment, and outcome variables. Patients were assessed for local, regional, and distant recurrences. Overall survival was calculated using the Kaplan-Meier method. Thirty-six patients met criteria for occult breast cancer. Most of these patients (77.8 %) had N1 disease. Fifty percent of cancers (n = 18) were estrogen receptor-positive; 12 (33.3 %) were triple-negative. All patients were evaluated with mammography. Thirty-five patients had breast ultrasound (97.2 %) and 33 (91.7 %) had an MRI. Thirty-four patients (94.4 %) were treated with chemotherapy and 33 (91.7 %) with radiotherapy. Twenty-seven patients (75.0 %) were treated with breast conservation. The median follow-up was 64 months. There were no local or regional failures. One distant recurrence occurred >5 years after diagnosis, resulting in a 5-years overall survival rate of 100 %. There were no significant survival differences between patients receiving breast conservation versus mastectomy (p = 0.7). Breast conservation-performed with contemporary imaging and multimodality treatment-provides excellent local control and survival for women with T0N+ breast cancer and can be safely offered instead of mastectomy.

Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort.

PubMed

Maskarinec, Gertraud; Dartois, Laureen; Delaloge, Suzette; Hopper, John; Clavel-Chapelon, Françoise; Baglietto, Laura

2017-08-01

Mammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent. Dense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses. Overall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33-1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR 1SD =2.25; 95% CI, 1.67-3.04) than in women reporting none (OR 1SD =1.41; 95% CI, 1.24-1.60; p heterogeneity =0.002). Similarly, effect modification by FHBC was observed using categories of PMD (p heterogeneity =0.02) with respective ORs of 15.16 (95% CI, 4.23-54.28) vs. 3.14 (95% CI, 1.89-5.22) for ≥50% vs. <10% PMD. The stronger association between mammographic density and breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density. Copyright © 2017 Elsevier Ltd. All rights reserved.

Benign breast disease and risk of thyroid cancer.

PubMed

Luo, Juhua; Hendryx, Michael; Nassir, Rami; Cheng, Ting-Yuan David; Lane, Dorothy; Margolis, Karen L

2017-09-01

It has been suggested that breast and thyroid diseases may be linked. The aim of this study was to investigate the association between benign breast disease and subsequent risk of thyroid cancer. Postmenopausal women (n = 133,875) aged 50-79 years were followed up for a mean of 14 years. Benign breast disease was defined by history of biopsy. Incident thyroid cancer cases were confirmed by medical record review. Multivariable Cox proportional hazard modeling was used to estimate hazard ratios. There were 370 incident thyroid cancer cases during the follow-up period. Compared to women without BBD, women with BBD had a significant increased risk of thyroid cancer after adjusting for potential confounders (HR 1.38 95% CI 1.10-1.73), especially for women with more than two biopsies (HR 1.59 95% CI 1.10-2.26). There were no significant differences in thyroid tumor size, stage or histologic types between women with and without BBD. Our large prospective study observed that postmenopausal women with BBD had an increased risk for thyroid cancer compared with women without BBD. A more detailed investigation of thyroid cancer risk according to different subtypes of benign breast disease is needed to better understand the association observed between thyroid and benign breast diseases.

DDT Exposure in Utero and Breast Cancer

PubMed Central

La Merrill, Michele; Krigbaum, Nickilou Y.; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M.

2015-01-01

Context: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation. Hypothesis: In utero exposure to DDT is associated with an increased risk of breast cancer. Design: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year). Setting and Participants: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study. Main Outcome Measure: Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured. Results: Maternal o,p′-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5–9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings. Conclusions: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk. PMID:26079774

DDT Exposure in Utero and Breast Cancer.

PubMed

Cohn, Barbara A; La Merrill, Michele; Krigbaum, Nickilou Y; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M

2015-08-01

Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation. In utero exposure to DDT is associated with an increased risk of breast cancer. This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year). Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study. Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured. Maternal o,p'-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings. This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.

Identifying Breast Cancer Oncogenes

DTIC Science & Technology

2009-10-01

study by Boehm et al. (2007) identified IKBKE as a breast cancer oncogene that cooperates with HMLE -MEKDD to replace the function of myr-AKT in...1-0767 TITLE: Identifying Breast Cancer Oncogenes ~ PRINCIPAL INVESTIGATOR: Yashaswi Shrestha...Identifying Breast Cancer Oncogenes 5a. CONTRACT NUMBER W81XWH-08-1-0767 5b. GRANT NUMBER BC083061 - PreDoc 5c. PROGRAM ELEMENT NUMBER 6

Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer

PubMed Central

Lorsy, Eva; Topuz, Aylin Sophie; Geisler, Cordelia; Stahl, Sarah; Garczyk, Stefan; von Stillfried, Saskia; Hoss, Mareike; Gluz, Oleg; Hartmann, Arndt; Knüchel, Ruth; Dahl, Edgar

2016-01-01

Dickkopf 3 (DKK3) has been associated with tumor suppression of various tumor entities including breast cancer. However, the functional impact of DKK3 on the tumorigenesis of distinct molecular breast cancer subtypes has not been considered so far. Therefore, we initiated a study analyzing the subtype-specific DKK3 expression pattern as well as its prognostic and functional impact with respect to breast cancer subtypes. Based on three independent tissue cohorts including one in silico dataset (n = 30, n = 463 and n = 791) we observed a clear down-regulation of DKK3 expression in breast cancer samples compared to healthy breast tissue controls on mRNA and protein level. Interestingly, most abundant reduction of DKK3 expression was detected in the highly aggressive basal breast cancer subtype. Analyzing a large in silico dataset comprising 3,554 cases showed that low DKK3 mRNA expression was significantly associated with reduced recurrence free survival (RFS) of luminal and basal-like breast cancer cases. Functionally, DKK3 re-expression in human breast cancer cell lines led to suppression of cell growth possibly mediated by up-regulation of apoptosis in basal-like but not in luminal-like breast cancer cell lines. Moreover, ectopic DKK3 expression in mesenchymal basal breast cancer cells resulted in partial restoration of epithelial cell morphology which was molecularly supported by higher expression of epithelial markers like E-Cadherin and down-regulation of mesenchymal markers such as Snail 1. Hence, we provide evidence that down-regulation of DKK3 especially promotes tumorigenesis of the aggressive basal breast cancer subtype. Further studies decoding the underlying molecular mechanisms of DKK3-mediated effects may help to identify novel targeted therapies for this clinically highly relevant breast cancer subtype. PMID:27467270

Deleted in breast cancer-1 (DBC-1) in the interface between metabolism, aging and cancer

PubMed Central

Chini, Eduardo Nunes; Chini, Claudia C. S.; Nin, Veronica; Escande, Carlos

2013-01-01

DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. Since alteration in cellular metabolism have been proposed to be the emerging ‘hallmark’ of cancer, it is possible that DBC1 may be implicated in the regulation of cancer cell energy metabolism. However, at this point any role of DBC1 in cancer is only speculative. In this review, we will discuss the new developments in DBC1 research, its molecular structure, regulatory roles and implication in metabolism, aging and cancer. PMID:23841676

Knowledge about breast cancer and hereditary breast cancer among nurses in a public hospital 1

PubMed Central

Prolla, Carmen Maria Dornelles; da Silva, Patrícia Santos; Netto, Cristina Brinckmann Oliveira; Goldim, José Roberto; Ashton-Prolla, Patricia

2015-01-01

OBJECTIVE: To assess the knowledge of nurses involved in the care of oncology patients in a public university hospital, regarding breast cancer and hereditary breast cancer, and to verify the use of such knowledge in their daily practice. METHODS: This is a descriptive cross-sectional study. Data were obtained through a structured, self-administered questionnaire. Out of 154 nurses, 137 (88.9%) agreed to participate in the study. Two questionnaires were excluded such that 135 questionnaires were analyzed. RESULTS: The global percentage of correct answers was not associated with age (p=0.173) or degree/specialization (p=0.815). Questions were classified into categories. In categories involving knowledge of established breast cancer risk factors and indicators of hereditary breast cancer, the rate of correct answers was 65.8% and 66.4%, respectively. On the practice of genetic counseling, 40.7% of those interviewed were not sure about the definition of genetic counseling and 78.5% reported never having identified or referred a patient at genetic risk for specialized risk assessment. Practice of educational actions regarding this subject was reported by 48.5% of those interviewed. CONCLUSION: This study reinforces the need to develop qualifying actions for nurses, so that strategies to control breast cancer become effective in their health care practice. PMID:25806636

Neuropeptide Y Y1 receptors meditate targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy.

PubMed

Li, Juan; Shen, Zheyu; Ma, Xuehua; Ren, Wenzhi; Xiang, Lingchao; Gong, An; Xia, Tian; Guo, Junming; Wu, Aiguo

2015-03-11

By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.

[Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer?].

PubMed

Sénéchal, Claire; Reyal, Fabien; Callet, Nasrine; This, Pascale; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Fourme, Emmanuelle

2016-03-01

In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Theranostics Targeting Metastatic Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0389 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Kevin Burgess CONTRACTING...ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 4. TITLE AND SUBTITLE Theranostics Targeting Metastatic Breast Cancer 5a...safe and effective interventions; (ii) elimination of mortality associated with metastatic breast cancer ; and, (iii) distinguishing aggressive breast

Are breast density and bone mineral density independent risk factors for breast cancer?

PubMed

Kerlikowske, Karla; Shepherd, John; Creasman, Jennifer; Tice, Jeffrey A; Ziv, Elad; Cummings, Steve R

2005-03-02

Mammographic breast density and bone mineral density (BMD) are markers of cumulative exposure to estrogen. Previous studies have suggested that women with high mammographic breast density or high BMD are at increased risk of breast cancer. We determined whether mammographic breast density and BMD of the hip and spine are correlated and independently associated with breast cancer risk. We conducted a cross-sectional study (N = 15,254) and a nested case-control study (of 208 women with breast cancer and 436 control subjects) among women aged 28 years or older who had a screening mammography examination and hip BMD measurement within 2 years. Breast density for 3105 of the women was classified using the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories, and percentage mammographic breast density among the case patients and control subjects was quantified with a computer-based threshold method. Spearman rank partial correlation coefficient and Pearson's correlation coefficient were used to examine correlations between BI-RADS breast density and BMD and between percentage mammographic breast density and BMD, respectively, in women without breast cancer. Logistic regression was used to examine the association of breast cancer with percentage mammographic breast density and BMD. All statistical tests were two-sided. Neither BI-RADS breast density nor percentage breast density was correlated with hip or spine BMD (correlation coefficient = -.02 and -.01 for BI-RADS, respectively, and -.06 and .01 for percentage breast density, respectively). Neither hip BMD nor spine BMD had a statistically significant relationship with breast cancer risk. Women with breast density in the highest sextile had an approximately threefold increased risk of breast cancer compared with women in the lowest sextile (odds ratio = 2.7, 95% confidence interval = 1.4 to 5.4); adjusting for hip or spine BMD did not change the association between breast density

PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT.

PubMed

Liu, Xue; Chen, Qian; Hu, Xu-Gang; Zhang, Xian-Chao; Fu, Ti-Wei; Liu, Qing; Liang, Yan; Zhao, Xi-Long; Zhang, Xia; Ping, Yi-Fang; Bian, Xiu-Wu

2016-10-01

Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues. Notably, PTP1B was positively associated with lymph node metastasis (LNM) and estrogen receptor (ER) status. In vitro, disturbing PTP1B expression obviously attenuated cell migration and invasion. On the contrary, PTP1B overexpression significantly increased migration and invasion of breast cancer cells. Mechanistically, PTP1B knockdown upregulated PTEN, accompanied with an abatement of AKT phosphorylation and the expression of matrix metalloproteinase 2 (MMP2) and MMP7. Conversely, forced expression of PTP1B reduced PTEN and increased AKT phosphorylation as well as the expression of MMP2 and MMP7. Notably, neither EMT nor stemness of breast cancer cells was regulated by PTP1B. We also found that PTP1B acted as an independent prognostic factor and predicted poor prognosis in ER-positive breast cancer patients. Taken together, our findings provide advantageous evidence for the development of PTP1B as a potential therapeutic target for breast cancer, especially for ER-positive breast cancer patients.

ABC1 Consensus Conference - a German Perspective: First International Consensus Conference on Advanced Breast Cancer (ABC1), Lisbon, November 5, 2011.

PubMed

Thomssen, Christoph; Marschner, Norbert; Untch, Michael; Decker, Thomas; Hegewisch-Becker, Susanna; Jackisch, Christian; Janni, Wolfgang; Hans-Joachim, Lück; von Minckwitz, Gunter; Scharl, Anton; Schneeweiss, Andreas; Tesch, Hans; Welt, Anja; Harbeck, Nadia

2012-02-01

A group of German breast cancer experts (medical oncologists and gynaecologists) reviewed and commented on the results of the first international 'Advanced Breast Cancer First Consensus Conference' (ABC1) for the diagnosis and treatment of advanced breast cancer. The ABC1 Conference is an initiative of the European School of Oncology (ESO) Metastatic Breast Cancer Task Force in cooperation with the EBCC (European Breast Cancer Conference), ESMO (European Society of Medical Oncology) and the American JNCI (Journal of the National Cancer Institute). The main focus of the ABC1 Conference was metastatic breast cancer (stage IV). The ABC1 consensus is based on the vote of 33 breast cancer experts from different countries and has been specified as a guideline for therapeutic practice by the German expert group. It is the objective of the ABC1 consensus as well as of the German comments to provide an internationally standardized and evidence-based foundation for qualified decision-making in the treatment of metastatic breast cancer.

Evaluation of the BT-1 serum assay for breast cancer.

PubMed

Whitehurst, M M; Aldenderfer, P H; Sooy, M M; Strelkauskas, A J

1999-01-01

The BT-1 assay which identifies a novel breast tumor associated serum analyte was performed for 143 patients previously diagnosed with breast cancer. Mucin tumor markers CA15-3/CA27-29 values were available for 50 patients and there was very minor overlap between patients positive by both tests. Patients' follow-up clinical status at sample draw was compared to BT-1 assay results. 27% of patients originally diagnosed as Stage II and 20% patients originally diagnosed as Stage III who were evaluated 'no disease' had positive BT-1 values. 8% patients diagnosed as Stage II had negative BT-1 results in samples drawn within 90 days of chemotherapy initiation, whereas 23% of patients diagnosed as Stage III cancer were BT-1 test positive within 90 days of chemotherapy initiation. 50% of patients tested before initial breast cancer surgery had positive BT-1 values, suggesting that the BT-1 assay may be useful in identification women with more advanced disease at diagnosis.

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

PubMed Central

Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Marchand, Loic Le; Goldberg, Mark S.; Teo, Soo H.; Taib, Nur A. M.; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W. M.; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D. P.

2016-01-01

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. PMID:27556229

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

PubMed

Horne, Hisani N; Chung, Charles C; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H; Ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Vachon, Celine; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Marchand, Loic Le; Goldberg, Mark S; Teo, Soo H; Taib, Nur A M; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W M; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D P; Easton, Douglas F; Chanock, Stephen J; Dunning, Alison M; Figueroa, Jonine D

2016-01-01

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling.

PubMed

Shrestha, Y; Schafer, E J; Boehm, J S; Thomas, S R; He, F; Du, J; Wang, S; Barretina, J; Weir, B A; Zhao, J J; Polyak, K; Golub, T R; Beroukhim, R; Hahn, W C

2012-07-19

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.

DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.

PubMed

Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

2014-04-01

Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

PubMed Central

Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y. Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

2014-01-01

Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β–induced expression of parathyroid hormone–like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho–TGF-β crosstalk in osteolytic bone metastasis. PMID:24590291

Breast cancer screening

MedlinePlus

Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... performed to screen women to detect early breast cancer when it is more likely to be cured. ...

The prognostic value of node status in different breast cancer subtypes

PubMed Central

Hou, Xin-Wei; Chi, Jiang-Rui; Ge, Jie; Wang, Xin; Cao, Xu-Chen

2017-01-01

Nodal metastases and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. However, the association between nodal metastases and BCS, and the prognostic value of nodal metastases in different BCS are still remains unclear. Our aim was to investigate the association between nodal metastases and BCS, and the prognostic value of nodal metastases in the different BCS. We found that the breast cancer subtype was closely associated with the pN stage. pN stage and breast cancer subtype were significantly associated with disease-free survival. The subgroup analysis showed that the patients in higher pN stage had a poor outcome than patients in lower pN stage in each breast cancer subtype. Furthermore, when the analysis was stratified by breast cancer subtype, we found that even in the same pN stage (pN0-pN2), there was significant survival difference among patients in different BCS, and Luminal A breast cancer patients had the best survival outcome. However, there were no significant survival difference between Luminal A patients and other breast cancer subtype when patients in pN3 stage. Thus, our study suggested that both lymph node status and molecular subtype played important roles in the outcome of breast cancer patients and they cannot replace each other. PMID:27999188

Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

PubMed

Kotsopoulos, Joanne; Huzarski, Tomasz; Gronwald, Jacek; Singer, Christian F; Moller, Pal; Lynch, Henry T; Armel, Susan; Karlan, Beth; Foulkes, William D; Neuhausen, Susan L; Senter, Leigha; Tung, Nadine; Weitzel, Jeffrey N; Eisen, Andrea; Metcalfe, Kelly; Eng, Charis; Pal, Tuya; Evans, Gareth; Sun, Ping; Lubinski, Jan; Narod, Steven A

2017-01-01

Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers. Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided. Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = 76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = 14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = 007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = 51). Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Association of proteasomal activity with metastasis in luminal breast cancer

NASA Astrophysics Data System (ADS)

Shashova, E. E.; Fesik, E. A.; Doroshenko, A. V.

2017-09-01

Chimotrypsin-like (ChTL) and caspase-like (CL) proteasomal activities were investigated in different variants of the tumor progression of luminal breast cancer. Patients with primary luminal breast cancer (n = 123) in stage T1-3N0-2M0 who had not received neoadjuvant treatment were included in this study. Proteasome ChTL and CL activities were determined in the samples of tumor and adjacent tissues. The coefficients of chymotrypsin-like (kChTL) and caspase-like (kCL) proteasome activity were also calculated as the ratio of the corresponding activity in the tumor tissue to activity in the adjacent tissue. ChTL, CL, kChTL and kCL in the tissues of luminal A and B breast cancer with lymphogenic metastasis were compared, and their association with hematogenous metastasis was evaluated. On the one hand, CL activity of proteasomes increased in luminal A breast cancer with extensive lymphogenic metastasis (N2), on the other hand it decreased in the luminal B subtype of cancer. The ratio of proteasomal activity in the tumor and adjacent tissues plays a significant role in the hematogenic pathway of breast cancer progression and is associated with poor metastatic-free survival.

Retrospective observation on contribution and limitations of screening for breast cancer with mammography in Korea: detection rate of breast cancer and incidence rate of interval cancer of the breast.

PubMed

Lee, Kunsei; Kim, Hyeongsu; Lee, Jung Hyun; Jeong, Hyoseon; Shin, Soon Ae; Han, Taehwa; Seo, Young Lan; Yoo, Youngbum; Nam, Sang Eun; Park, Jong Heon; Park, Yoo Mi

2016-11-18

The purpose of this study was to determine the benefits and limitations of screening for breast cancer using mammography. Descriptive design with follow-up was used in the study. Data from breast cancer screening and health insurance claim data were used. The study population consisted of all participants in breast cancer screening from 2009 to 2014. Crude detection rate, positive predictive value and sensitivity and specificity of breast cancer screening and, incidence rate of interval cancer of the breast were calculated. The crude detection rate of breast cancer screening per 100,000 participants increased from 126.3 in 2009 to 182.1 in 2014. The positive predictive value of breast cancer screening per 100,000 positives increased from 741.2 in 2009 to 1,367.9 in 2014. The incidence rate of interval cancer of the breast per 100,000 negatives increased from 51.7 in 2009 to 76.3 in 2014. The sensitivities of screening for breast cancer were 74.6% in 2009 and 75.1% in 2014 and the specificities were 83.1% in 2009 and 85.7% in 2014. To increase the detection rate of breast cancer by breast cancer screening using mammography, the participation rate should be higher and an environment where accurate mammography and reading can be performed and reinforcement of quality control are required. To reduce the incidence rate of interval cancer of the breast, it will be necessary to educate women after their 20s to perform self-examination of the breast once a month regardless of participation in screening for breast cancer.

Expression characteristic of CXCR1 in different breast tissues and the relevance between its expression and efficacy of neo-adjuvant chemotherapy in breast cancer.

PubMed

Xue, Miao-Qun; Liu, Jun; Sang, Jian-Feng; Su, Lei; Yao, Yong-Zhong

2017-07-25

To investigate chemokine receptor CXCR1 expression characteristic in different breast tissues and analyze the relationship between CXCR1 expression changes in breast cancer tissue and efficacy of neo-adjuvant chemotherapy. Chemokine receptor CXCR1 was lowly expressed in normal breast tissues and breast fibroadenoma, but highly expressed in breast cancer. It was significantly correlated with pathological stage, tumor cell differentiation, and lymph node metastasis (P < 0.05). After neo-adjuvant chemotherapy, CXCR1 expression in breast cancer tissues decreased. Among these 104 breast cancer patients with different molecular subtypes, the survival rate with Luminal A was the highest, followed by the Luminal B breast cancer, TNBC was the worst. 104 cases with breast carcinoma, 20 cases with normal breast and 20 cases with breast fibroadenoma were included and followed up. Immunohistochemistry was used to detect the expression of CXCR1 in the various tissues. The relationship between the CXCR1 expression changes in breast cancer biopsies and surgical specimens, as well as the efficacy of neo-adjuvant chemotherapy, was analyzed. Chemokine receptor CXCR1 could be used as an indicator to predict benign or malignant breast disease, and it can even predict the malignancy degree of breast cancer, as well as its invasive ability and prognosis.

Real-world impact of non-breast cancer-specific death on overall survival in resectable breast cancer.

PubMed

Fu, Jianfei; Wu, Lunpo; Jiang, Mengjie; Li, Dan; Jiang, Ting; Fu, Wei; Wang, Liangjing; Du, Jinlin

2017-07-01

The real-world occurrence rate of non-breast cancer-specific death (non-BCSD) and its impact on patients with breast cancer are poorly recognized. Women with resectable breast cancer from 1990 to 2007 in the Surveillance, Epidemiology, and End Results database (n = 199,963) were analyzed. The outcome events of breast cancer were classified as breast cancer-specific death (BCSD), non-BCSD, or survival. Binary logistics was used to estimate the occurrence rates of non-BCSD and BCSD with different clinicopathological factors. The Gray method was used to measure the cumulative incidence of non-BCSD and BCSD. The ratio of non-BCSDs to all causes of death and stacked cumulative incidence function plots were used to present the impact of non-BCSD on overall survival (OS). Models of Cox proportional hazards regression and competing risk regression were compared to highlight the suitable model. There were 12,879 non-BCSDs (6.44%) and 28,784 BCSDs (14.39%). The oldest age group (>62 years), black race, and a single or divorced marital status were associated with more non-BCSDs. With adjustments for age, a hormone receptor-positive (HoR+) status was no longer related to increased non-BCSDs. In patients with grade 1, stage I disease and an HoR+ status as well as the oldest subgroup, a great dilution of non-BCSD on all causes of death could be observed, and this led to incorrect interpretations. The inaccuracy, caused by the commonly used Cox proportional hazards model, could be corrected by a competing risk model. OS was largely impaired by non-BCSD during early breast cancer. For some future clinical trial planning, especially for the oldest patients and those with HoR+ breast cancer, non-BCSD should be considered a competing risk event. Cancer 2017;123:2432-43. © 2017 American Cancer Society. © 2017 American Cancer Society.

An integrated genomic analysis of Tudor domain-containing proteins identifies PHD finger protein 20-like 1 (PHF20L1) as a candidate oncogene in breast cancer.

PubMed

Jiang, Yuanyuan; Liu, Lanxin; Shan, Wenqi; Yang, Zeng-Quan

2016-02-01

Tudor domain-containing proteins (TDRDs), which recognize and bind to methyl-lysine/arginine residues on histones and non-histone proteins, play critical roles in regulating chromatin architecture, transcription, genomic stability, and RNA metabolism. Dysregulation of several TDRDs have been observed in various types of cancer. However, neither the genomic landscape nor clinical significance of TDRDs in breast cancer has been explored comprehensively. Here, we performed an integrated genomic and transcriptomic analysis of 41 TDRD genes in breast cancer (TCGA and METABRIC datasets) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. Among seven TDRDs that had the highest frequency (>10%) of gene amplification, the plant homeodomain finger protein 20-like 1 (PHF20L1) was the most commonly amplified (17.62%) TDRD gene in TCGA breast cancers. Different subtypes of breast cancer had different patterns of copy number and expression for each TDRD. Notably, amplification and overexpression of PHF20L1 were more prevalent in aggressive basal-like and Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. Furthermore, knockdown of PHF20L1 inhibited cell proliferation in PHF20L1-amplified breast cancer cell lines. PHF20L1 protein contains N-terminal Tudor and C-terminal plant homeodomain domains. Detailed characterization of PHF20L1 in breast cancer revealed that the Tudor domain likely plays a critical role in promoting cancer. Mechanistically, PHF20L1 might participate in regulating DNA methylation by stabilizing DNA methyltransferase 1 (DNMT1) protein in breast cancer. Thus, our results demonstrated the oncogenic potential of PHF20L1 and its association with poor prognostic parameters in breast cancer. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling

PubMed Central

Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; Thomas, Sapana R.; He, Frank; Du, Jinyan; Wang, Shumei; Barretina, Jordi; Weir, Barbara A.; Zhao, Jean J.; Polyak, Kornelia; Golub, Todd R.; Beroukhim, Rameen; Hahn, William C.

2011-01-01

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified PAK1 as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of Merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation. PMID:22105362

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

PubMed

Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B; Rudolph, Anja; Schmutzler, Rita K; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A; Easton, Douglas F; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A; Schmidt, Marjanka K; van der Baan, Frederieke H; Spurdle, Amanda B; Walker, Logan C; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B; Olopade, Olufunmilayo I; Nussbaum, Robert L; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Arun, Banu K; Karlan, Beth Y; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K; Miron, Alex; Southey, Melissa C; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Ding, Yuan Chun; Neuhausen, Susan L; Hansen, Thomas V O; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E; Blazer, Kathleen R; Weitzel, Jeffrey N; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D Gareth R; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M John; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V; Ellis, Steve; Cole, Trevor; Godwin, Andrew K; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L; Rodriguez, Gustavo C; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A M; Meijers-Heijboer, Hanne E J; van der Hout, Annemarie H; Vreeswijk, Maaike P G; Hoogerbrugge, Nicoline; Ausems, Margreet G E M; van Doorn, Helena C; Collée, J Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R; Olswold, Curtis; Couch, Fergus J; Lindor, Noralane M; Wang, Xianshu; Szabo, Csilla I; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C; Friedman, Eitan

2015-01-01

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. ©2014 American Association for Cancer Research.

Validation of a measurement tool to assess awareness of breast cancer.

PubMed

Linsell, Louise; Forbes, Lindsay J L; Burgess, Caroline; Kapari, Marcia; Thurnham, Angela; Ramirez, Amanda J

2010-05-01

Until now, there has been no universally accepted and validated measure of breast cancer awareness. This study aimed to validate the new Breast Cancer Awareness Measure (BCAM) which assesses, using a self-complete questionnaire, knowledge of breast cancer symptoms and age-related risk, and frequency of breast checking. We measured the psychometric properties of the BCAM in 1035 women attending the NHS Breast Screening Programme: acceptability was assessed using a feedback questionnaire (n=292); sensitivity to change after an intervention promoting breast cancer awareness (n=576), and test-retest reliability (n=167). We also assessed readability, and construct validity using the 'known-groups' method. The readability of the BCAM was high. Over 90% of women found it acceptable. The BCAM was sensitive to change: there was an increase in the proportion of women obtaining the full score for breast cancer awareness one month after receiving the intervention promoting breast cancer awareness; this was greater among those who received a more intensive version (less intensive version (booklet): 9.3%, 95% confidence interval (CI): 4.5-14.1%; more intensive version (interaction with health professional plus booklet): 30%, 95% CI: 23.4-36.6%). Test-retest reliability of the BCAM was moderate to good for most items. Cancer experts had higher levels of cancer awareness than non-medical academics (50% versus 6%, p=0.001), indicating good construct validity. The BCAM is a valid and robust measure of breast cancer awareness suitable for use in surveys of breast cancer awareness in the general population and to evaluate the impact of awareness-raising interventions. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mu, Haixi; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016; Wang, Na

Our previous study showed that PLCD1 significantly decreases cell proliferation and affects cell cycle progression in breast cancer cells. In the present study, we aimed to investigate its functional and molecular mechanisms, and whether or not can become a new target for gene therapies. We found reduced PLCD1 protein expression in breast tumor tissues compared with paired surgical margin tissues. PLCD1 promoter CpG methylation was detected in 55 of 96 (57%) primary breast tumors, but not in surgical-margin tissues and normal breast tissues. Ectopic expression of PLCD1 inhibited breast tumor cell proliferation in vivo by inducing apoptosis and suppressed tumormore » cell migration by regulating cytoskeletal reorganization proteins including RhoA and phospho-cofilin. Furthermore, we found that PLCD1 induced p53 accumulation, increased p27 and p21 protein levels, and cleaved PARP. Finally, we constructed an adenoviral vector expressing PLCD1 (AdH5-PLCD1), which exhibited strong cytotoxicity in breast cancer cells. Our findings provide insights into the development of PLCD1 gene therapies for breast cancer and perhaps, other human cancers. - Highlights: • PLCD1 is downregulated via hypermethylation in breast cancer. • PLCD1 suppressed cell migration by regulating cytoskeletal reorganization proteins. • Adenovirus AdHu5-PLCD1 may be a novel therapeutic option for breast cancer.« less

Antiperspirant use and the risk of breast cancer.

PubMed

Mirick, Dana K; Davis, Scott; Thomas, David B

2002-10-16

The rumor that antiperspirant use causes breast cancer continues to circulate the Internet. Although unfounded, there have been no published epidemiologic studies to support or refute this claim. This population-based case- control study investigated a possible relationship between use of products applied for underarm perspiration and the risk for breast cancer in women aged 20-74 years. Case patients (n = 813) were diagnosed between November 1992 and March 1995; control subjects (n = 793) were identified by random digit dialing and were frequency-matched by 5-year age groups. Product use information was obtained during an in-person interview. Odds ratios (ORs) and 95% confidence intervals were estimated by the use of conditional logistic regression. P values were determined with the Wald chi(2) test. All statistical tests were two-sided. The risk for breast cancer did not increase with any of the following activities: 1) antiperspirant (OR = 0.9; P =.23) or deodorant (OR = 1.2; P =.19) use; 2) product use among subjects who shaved with a blade razor; or 3) application of products within 1 hour of shaving (for antiperspirant, OR = 0.9 and P =.40; for deodorant, OR = 1.2 and P =.16). These findings do not support the hypothesis that antiperspirant use increases the risk for breast cancer.

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

DTIC Science & Technology

2011-09-01

breast-cancer-targeted nuclear drug delivery carriers , but we found that the ability of the PEI to disrupt the endosome/lysosome membrane was not...AD_________________ Award Number: W81XWH-09-1-0502 TITLE: Breast Cancer-Targeted Nuclear Drug ...Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy PRINCIPAL INVESTIGATOR: Youqing Shen, Ph.D

GSE1 negative regulation by miR-489-5p promotes breast cancer cell proliferation and invasion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chai, Peng, E-mail: chaiyisheng0508@sina.com; Tian, Jingzhong; Zhao, Deyin

Gse1 coiled-coil protein (GSE1), also known as KIAA0182, is a proline rich protein. However, the function of GSE1 is largely unknown. In this study, we reported that GSE1 is overexpression in breast cancer and silencing of GSE1 significantly suppressed breast cancer cells proliferation, migration and invasion. Furthermore, GSE1 was identified as a direct target of miR-489-5p, which is significantly reduced in breast cancer tissues. In addition, forced expression of miR-489-5p suppressed breast cancer cells proliferation, migration and invasion. Moreover, depletion of GSE1 by siRNAs significantly abrogated the enhanced proliferation, migration and invasion of breast cancer cells consequent to miR-489-5p depletion.more » Taken together, these findings suggest that GSE1 may function as a novel oncogene in breast cancer and it can be regulated by miR-489-5p. - Highlights: • GSE1 is overexpressed in breast cancer and increased GSE1 expression predicts poor prognosis in breast cancer patients. • Knockdown of GSE1 inhibits breast cancer cell proliferation, migration and invasion. • GSE1 is a direct target of miR-489-5p. • Forced expression of miR-489-5p inhibits breast cancer cell proliferation, migration and invasion.« less

Breast Cancer Overview

MedlinePlus

... are here Home > Types of Cancer > Breast Cancer Breast Cancer This is Cancer.Net’s Guide to Breast Cancer. Use the menu below to choose the Overview/ ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer Introduction Statistics Medical Illustrations Risk Factors and Prevention ...

Prevention of breast cancer.

PubMed

Olver, Ian N

2016-11-21

Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta-analysis

PubMed Central

Graff, Rebecca E.; Ursin, Giske; dos Santos Silva, Isabel; McCormack, Valerie; Baglietto, Laura; Vachon, Celine; Bakker, Marije F.; Giles, Graham G.; Chia, Kee Seng; Czene, Kamila; Eriksson, Louise; Hall, Per; Hartman, Mikael; Warren, Ruth M. L.; Hislop, Greg; Chiarelli, Anna M.; Hopper, John L.; Krishnan, Kavitha; Li, Jingmei; Li, Qing; Pagano, Ian; Rosner, Bernard A.; Wong, Chia Siong; Scott, Christopher; Stone, Jennifer; Maskarinec, Gertraud; Boyd, Norman F.; van Gils, Carla H.

2014-01-01

Background Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. Methods We conducted a meta-analysis of 13 case–control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. Results Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. Conclusions The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area. PMID:24816206

Overexpression of SERBP1 (Plasminogen activator inhibitor 1 RNA binding protein) in human breast cancer is correlated with favourable prognosis

PubMed Central

2012-01-01

Background Plasminogen activator inhibitor 1 (PAI-1) overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1, a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. Methods Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25), and in matched pairs of normal (n = 7) and cancerous breast tissues (n = 7). SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs), an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n = 2) and malignant (n = 6) mammary cell lines as well as breast carcinoma lysates (n = 16) were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal (n = 10) and cancerous (n = 10) breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. Results SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008) between abundant SERBP1 expression in breast carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09) towards favourable prognosis when SERBP1 was overexpressed in breast cancer. Conclusions The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a novel breast tumour

Breast Cancer -- Male

MedlinePlus

... Home > Types of Cancer > Breast Cancer in Men Breast Cancer in Men This is Cancer.Net’s Guide to Breast Cancer in Men. Use the menu below to choose ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer in Men Introduction Statistics Risk Factors and Prevention ...

Targeting ESR1-Mutant Breast Cancer

DTIC Science & Technology

2015-09-01

Award Number: W81XWH-14-1-0360 TITLE: Targeting ESR1 -Mutant Breast Cancer PRINCIPAL INVESTIGATOR: Geoffrey L. Greene, Ph.D. CONTRACTING...ADDRESS. 1. REPORT DATE September 2015 2. REPORT TYPE Annual 3. DATES COVERED 1 Sep 2014 - 31 Aug 2015 4. TITLE AND SUBTITLE Targeting ESR1 -Mutant...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The hypothesis of this proposal is that LBD mutations in ESR1 promote resistance to current FDA

The Treatment of BRCA1/2 Hereditary Breast Cancer and Sporadic Breast Cancer with Poly(ADP-ribose) PARP-1 Inhibitors and Chemotherapy

DTIC Science & Technology

2008-09-01

American population d) D) Obesity, and breast cancer J. of Nursing and Bariatric Surgery . 2008 submitting. This paper uses in part mechanisms worked...National Med. Society. 2008 submitting D) Obesity, and breast cancer J. of Nursing and Bariatric Surgery . 2008 submitting Abstracts: A) De Soto JA...submitting De Soto JA. Obesity, breast cancer and bariatric surgery . J. of Nursing and Bariatric Surgery . 2008 submitting Davis JH, De Soto JA

Nutritional channels in breast cancer.

PubMed

Godoy, Alejandro; Salazar, Katherine; Figueroa, Carlos; Smith, Gary J; de Los Angeles Garcia, Maria; Nualart, Francisco J

2009-09-01

Breast cancers increase glucose uptake by increasing expression of the facilitative glucose transporters (GLUTs), mainly GLUT1. However, little is known about the relationship between GLUT1 expression and malignant potential in breast cancer. In this study, expression and subcellular localization of GLUT1 was analysed in vivo in breast cancer tissue specimens with differing malignant potential, based on the Scarff-Bloom-Richardson (SBRI, II, III) histological grading system, and in vitro in the breast cancer cell lines, MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts in nude athymic BALB/c male mice. In situ hybridization analyses demonstrated similar levels of GLUT1 mRNA expression in tissue sections from breast cancers of all histological grades. However, GLUT1 protein was expressed at higher levels in grade SBRII cancer, compared with SBRI and SBRIII, and associated with the expression of the proliferation marker PCNA. Immunolocalization analyses in SBRII cancers demonstrated a preferential localization of GLUT1 to the portions of the cellular membrane that faced neighbouring cells and formed 'canaliculi-like structures', that we hypothesize could have a potential role as 'nutritional channels'. A similar pattern of GLUT1 localization was observed in confluent cultures of MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts, but not in the normal breast epithelial cell line HMEC. However, no relationship between GLUT1 expression and malignant potential of human breast cancer was observed. Preferential subcellular localization of GLUT1 could represent a physiological adaptation of a subset of breast cancer cells that form infiltrative tumours with a nodular growth pattern and that therefore need a major diffusion of glucose from blood vessels.

High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells

PubMed Central

Daniel, Jewel; Coulter, Jonathan; Woo, Ju-Hyung; Wilsbach, Kathleen; Gabrielson, Edward

2011-01-01

Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 contribute to the ability of breast cancer cells to tolerate this aneuploidy. Reducing Mps1 levels in cultured human breast cancer cells by RNAi resulted in aberrant mitoses, induction of apoptosis, and decreased ability of human breast cancer cells to grow as xenografts in nude mice. Remarkably, breast cancer cells that survive reductions in levels of Mps1 have relatively less aneuploidy, as measured by copies of specific chromosomes, compared with cells that have constitutively high levels of Mps1. Thus, high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy. PMID:21402910

High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells.

PubMed

Daniel, Jewel; Coulter, Jonathan; Woo, Ju-Hyung; Wilsbach, Kathleen; Gabrielson, Edward

2011-03-29

Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 contribute to the ability of breast cancer cells to tolerate this aneuploidy. Reducing Mps1 levels in cultured human breast cancer cells by RNAi resulted in aberrant mitoses, induction of apoptosis, and decreased ability of human breast cancer cells to grow as xenografts in nude mice. Remarkably, breast cancer cells that survive reductions in levels of Mps1 have relatively less aneuploidy, as measured by copies of specific chromosomes, compared with cells that have constitutively high levels of Mps1. Thus, high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy.