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

BRCA1突变型和散发性基底细胞样癌的生物学与治疗 发生在携带BRCA1突变的女性身上的癌症有一种特有的表型，主要是 低分化、高级别浸润性导管癌，不表达HR或PR，也没有 ErbB2基因的扩增。基因表达阵列分析表明，这些BRCA1突变的癌症表现出 与基底细胞样癌(BLC)相同的基因表达谱，BLC是高级别KR(-)、PR的不同子集 (-)，Her2(-)肿瘤占人类乳腺癌的-15%。这些观察结果表明， BRCA 1突变体和散发性BLC具有相似的功能分子表型。作为BRCA1突变体 肿瘤细胞在DNA修复和非活动X染色体的表观稳定性方面表现出明显的缺陷，并 以对顺铂等DNA交联剂的高度敏感性为特征，BLC]还可能 分享这些功能。我们项目的目标是利用我们对BRCA 1生物学的知识来洞察 BLC的生物学，并确定特定的生理脆弱性，将指导更多 针对这一组侵袭性乳腺癌的有效治疗策略。前两个目标是为了分析 BLC和BRCA-1基因组稳定性、DNA修复和异染色质维持的特异性 突变，癌症样本，以表征他们的功能相似和不同。第三个目标是 评估一组患有ER(-)、PR(-)、Her2(-)乳腺癌的女性的反应，其中大多数 应该是BLC，在术前II期治疗试验中以顺铂为主，将任何 在前两个目标中验证的信息量生物学分析具有治疗反应。

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.