Abstract 2750: Modulation of BRCA1 expression as a preventative method for BRCA1-associated breast cancer

Abstract

Abstract Background: Women who inherited a BRCA1 mutation face a high lifetime risk of developing breast cancer estimated at 80% vs. 11% in the general population. Current prevention options are limited to prophylactic surgery and chemoprevention with tamoxifen. It is believed that a haploinsufficient state is responsible for the predisposition to cancer among BRCA1 mutation carriers. BRCA1 helps maintain genomic integrity through participating in the cellular response to DNA damage, specifically in the repair of double-stranded DNA breaks. Thus, factors which increase the physiologic expression of the normal gene and normalize protein levels may mitigate the effect of the mutation and decrease cancer risk. Objectives: The objectives of this study are: 1) to determine whether BRCA1 mRNA expression from peripheral blood lymphocytes (as well as the corresponding protein levels) differ in women with and without a BRCA1 mutation; 2) to correlate BRCA1 mRNA and protein levels with various factors, including reproductive, hormonal, and anthropometric factors as well as mutation type; and 3) to identify a minimal classifier gene set that predicts BRCA1 mutation status in the general population. Methodology: We enrolled 14 women with and 36 without a BRCA1 mutation. All participants completed a research questionnaire and standardized procedures were used to collect anthropometric measurements. Blood samples were collected for white blood cell isolation. BRCA1 mRNA was quantified using the Nanostring nCounter Analysis System and the Human Cancer Reference Kit, a panel of 230 cancer-associated genes. The gene expression data set will be used to identify a minimal gene classifier that predicts BRCA1 mutation status. BRCA1 protein levels will be determined using Western blot. Results: Mean BRCA1 expression was significantly lower for mutation carriers vs. non-carriers (139 vs. 157 counts; P = 0.02). Western blot experiments and analyses of predictors of expression are underway. Conclusions and Significance: These results provide important preliminary evidence that BRCA1 mutation carriers have lower peripheral white blood cell BRCA1 mRNA expression compared to non-carriers. Future studies can utilize peripheral blood samples from BRCA1 mutation carriers to evaluate whether lifestyle factors, such as diet and physical activity, may modulate BRCA1 levels and potentially modify disease risk. Our findings contribute to a program of research aimed at providing evidence-based lifestyle prevention strategies for high-risk women. Citation Format: Rania Chehade, Rachael Pettapiece-Phillips, Mohammad Akbari, Leonardo Salmena, Steven Narod, Joanne Kotsopoulos. Modulation of BRCA1 expression as a preventative method for BRCA1-associated breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2750. doi:10.1158/1538-7445.AM2015-2750