Molecular basis of genomic instability in aggressive basal-like breast cancer

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DESCRIPTION (provided by applicant): The National Cancer Institute reports that each year more than 211,000 American women are diagnosed with breast cancer (NCI, 2007). Two crucial components in clinical management of this disease are prediction of patient outcome and treatment response. Recently, expression profiling revealed new and promising classifications of breast cancer, which includes a subtype denoted basal-like breast carcinoma (BBC) (Perou et al., 2000; Sorlie et al., 2001). Notably, BBCs are associated with a comparatively worse disease-free survival (Rakha et al., 2008). This tumor subtype is typified as being "triple-negative" for the estrogen receptor, the progesterone receptor, and HER-2, meaning that the majority of BBCs cannot be managed with existing targeted treatments (trastuzumab and hormonal treatments) (Anders and Carey, 2008). Preliminary work in our lab and by others has identified notable molecular defects in BBCs that are indicative of a dysfunctional DNA repair system. For example, we find that BBCs possess increased numbers of low-level DNA copy-number alterations relative to the other breast cancer subtypes (Bergamaschi et al., 2006). In addition, we and others have found that the BBC pattern of genomic change and numerous other notable similarities exist between this aggressive cancer subtype and the tumors of germline carriers of BCRA1 mutations, similarities not shared with the other classes of breast cancer (reviewed in Tuner and Reis-Filho, 2006). These findings are particularly interesting as BRCA1 is known to play an important role in DNA repair and suggest that BRCA1 or components of the BRCA1 pathway are defective in BBC cells. Given distinct patterns of genomic alteration in basal-like breast carcinomas (BBCs) and their similarity to hereditary BRCA1-mutant tumors, we hypothesize that BBCs have an underlying defect in DNA repair, possibly relating to BRCA1, which might be exploitable therapeutically. The specific aims of this proposal are to (1) characterize DNA repair defects in BBC cells; (2) evaluate expression and function of BRCA1 in BBC cells; and (3) identify BBC-selective chemical and genetic vulnerabilities. This research is intended to provide a better understanding of the molecular underpinnings of BBC genomic instability and lay the foundation for BBC therapies, which are currently limited. PUBLIC HEALTH RELEVANCE: Breast cancer is a disease which has a profound impact on the health of women and some men throughout the world. Recently, powerful analytical tools have identified a subset of breast cancers that are more likely to result in poor patient outcome and for which treatment options are limited. We propose to study the molecular features of and possible therapeutics for this aggressive subtype of breast cancer.