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

BRCA 1突变体和散发性基底细胞样癌的生物学和治疗 在携带BRCA 1突变的女性中发生的癌症具有特征性表型，大多数是 低分化、高级别浸润性导管癌不表达HR或PR， erbB 2的纯化。基因表达阵列分析表明，这些BRCA 1突变型癌症显示， 与基底细胞样癌（BLC）相同的基因表达谱，是高级别KR（-），PR（-），PR（-），PR（-），PR（-）和PR（-）的一个独特子集。 (-)Her 2（-）肿瘤占人类乳腺癌的约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。作为BRCA 1突变体 肿瘤细胞在DNA修复和失活X染色体遗传稳定性方面表现出明显缺陷， 其特征在于对DNA交联剂如顺铂的敏感性提高，BLC还可以 分享这些特点。我们项目的目标是利用我们对BRCA 1生物学的了解， BLC的生物学，并确定特定的生理弱点，这将指导更多的发展 有效的治疗策略，这组侵略性乳腺癌。前两个目的是分析 在BLC和BRCA 1中基因组稳定性、DNA修复和异染色质维持的特定方面- 突变体，癌症样本，以表征其功能的相似性和差异。第三个目标是 评估ER（-）、PR（-）、Her 2（-）乳腺癌女性队列的缓解情况，其中大多数 应该是BLC，顺铂在II期术前治疗试验中， 在前两个目标中验证的信息性生物测定与治疗反应。

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.