Biology and treatment of BRCA1 mutant and sporadic Basal-like cancersThe cancers that arise in women harboring BRCA1 mutations have a characteristic phenotype, being mostlypoorly differentiated, high grade invasive ductal carcinomas that do not express HR or PR and do not haveamplifiation of erbB2. Gene expression array analysis has shown that these BRCA1-mutant cancers displaythe 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 theBRCA 1-mutant and sporadic BLC share a similar functional molecular phenotype. As BRCA1 -mutanttumor cells show clear defects in DNA repair and epigcnetic stability of the inactive X chromosome, and arecharacterized by heightened sensitivity to DNA cross linking agents such as cis-platinum, the BLC] may alsoshare these features. The goal of our project is to use our knowledge of BRCA 1 biology to gain insight intothe biology of BLC and identify specific physiologic vulnerabilities that will guide the development of moreeffective treatment strategies for this group of aggressive breast cancers. The first two aims arc to assayspecific 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 i s toevaluate the response of a cohort of women with ER(-), PR(-), Her2(-) breast cancers, of which the majorityshould be BLC, to cis-platinum in a phase II pre-operative treatment trial, correlate the results of anyinformative biological assays validated in the first two aims with treatment response.
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