Biology and treatment of Brca1-Associated and Sporadic Basal-Like cancers

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Biology and treatment of BRCA1 mutant and sporadic Basal-like cancers The cancers that arise in women harboring BRCA1 mutations have a characteristic phenotype, being mostly poorly differentiated, high grade invasive ductal carcinomas that do not express HR or PR and do not have amplifiation of erbB2. Gene expression array analysis has shown that these BRCA1-mutant cancers display the same gene expression profile as the basal-like cancers (BLC), a distinct subset of high grade KR(-), PR (-), Her2(-) tumors that account for -15% of human breast cancers. These observations suggest that the BRCA 1-mutant and sporadic BLC share a similar functional molecular phenotype. As BRCA1 -mutant tumor cells show clear defects in DNA repair and epigcnetic stability of the inactive X chromosome, and are characterized by heightened sensitivity to DNA cross linking agents such as cis-platinum, the BLC] may also share these features. The goal of our project is to use our knowledge of BRCA 1 biology to gain insight into the biology of BLC and identify specific physiologic vulnerabilities that will guide the development of more effective treatment strategies for this group of aggressive breast cancers. The first two aims arc to assay specific aspects of genomic stability, DNA repair and heterochromatin maintenance in BLC and BRCA 1 - mutant, cancer samples to characterize their functional similarities and differences. The third aim is to evaluate the response of a cohort of women with ER(-), PR(-), Her2(-) breast cancers, of which the majority should be BLC, to cis-platinum in a phase II pre-operative treatment trial, correlate the results of any informative biological assays validated in the first two aims with treatment response.