Biology and treatment of Brca1-Associated and Sporadic Basal-like Cancers

项目]：BRCA1突变和散发性基底细胞样癌的生物学和治疗 发生在携带BRCA1突变的女性身上的癌症有一个特征的表型，大多是低分化、高级别的浸润性导管癌，不表达HR或PR，也没有erbB2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样癌(BLC)相同的基因表达谱，基底样癌是高级别KR(-)、PR(-)、Her2(-)肿瘤的不同子集，占人类乳腺癌的-15%。这些观察表明，BRCA 1突变体和散发性BLC具有相似的功能分子表型。由于BRCA1突变的肿瘤细胞在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，并且对DNA交联剂如顺铂具有高度的敏感性，[BLC]也可能具有这些特征。我们项目的目标是利用我们对BRCA 1生物学的知识来深入了解BLC的生物学，并确定特定的生理脆弱性，这些脆弱性将指导对这一组侵袭性乳腺癌制定更有效的治疗策略。前两个目的是在BLC和BRCA 1突变的癌症样本中检测基因组稳定性、DNA修复和异染色质维持的特定方面，以表征它们功能的异同。第三个目标是评估一组ER(-)、PR(-)、Her2(-)乳腺癌患者(其中大多数应该是BLC)在手术前II期治疗试验中对顺铂的反应，将前两个目标中验证的任何信息丰富的生物检测结果与治疗反应相关联。

Project ]: 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.