Abstract P2-06-03: A Polymorphic AAAG Repeat in the Estrogen Receptor-Related-Gamma Gene May Represent a Breast Cancer Predisposition Biomarker

Abstract

Background: There is a strong genetic component to breast cancer, which is the most common neoplasm in women; however current risk markers are few, accounting for less than 10% of breast cancer cases. This means that the majority of familial breast cancers remain unexplained. Our laboratory has studied microsatellite polymorphisms for many years, and we developed techniques to assay these understudied regions of the genome en masse and individually via shot-gun methods to rapidly identify those that are likely to be polymorphic and therefore potentially contribute to phenotype. Material and Methods: Using these novel approaches, we identified a polymorphic AAAG microsatellite repeat in the estrogen-related receptor gamma (ERR-γ) that is expanded in -10% of the general population. We genotyped over 300 individuals and found a longer allelic version (13+ repeat copies) in 14.3% of breast cancer patients, compared to only 4.8% in cancer-free individuals. We computationally identified 22 transcription factors that could bind directly to this AAAG repeat and the surrounding region. We hypothesized that the AAAG-containing region might serve as a promoter for ERR-y. Results: We found a statistically significant number of breast cancer patients with the expanded AAAG allele, and preliminary experiments confirm that the AAAG-containing region of ERR-γ does indeed drive reporter gene expression in estrogen receptor positive (ER+) MCF-7 breast cancer cells. This was not the case for the ER-breast cancer cells (MDA-MB-231) we also examined. Our initial assessments also revealed that SKBR-3 breast cancer cells are naturally heterozygotic for the long and short allelic versions of the AAAG repeat. Our ongoing studies involve knockdown of transcription factors in MCF-7 cells that abrogate the endogenous expression of ERR-γ. Discussion: The role of microsatellites in cancer is well defined for colon cancer, but few studies have been conducted to examine the contribution of these simple sequence repeats in breast cancer. We discovered a polymorphic AAAG repeat in the ERR-γ gene, and our studies indicate that a longer version of this repeat is more prevalent in the genomes of breast cancer patients. Based on our assessment, this allele carries a 2.98 relative risk for the development of breast cancer. The higher incidence of this putative biomarker in breast cancer patients may be a result of altered ERR-γ expression, as the AAAG-containing sequence can drive reporter expression. If the frequency of this potentially predictive marker is sustained in a larger population, and the mechanism by which it confers the cancer phenotype can be identified, it may contribute substantially as a biomarker offering surveillance, prophylactic surgery, and chemoprevention options to patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-03.