Molecular basis of genomic instability in aggressive basal-like breast cancer

描述（由申请人提供）：美国国家癌症研究所报告，每年有超过211，000名美国妇女被诊断患有乳腺癌（NCI，2007）。这种疾病的临床管理中的两个关键组成部分是预测患者的结果和治疗反应。最近，表达谱揭示了乳腺癌的新的和有希望的分类，其包括称为基底样乳腺癌（BBC）的亚型（Perou et al.，2000; Sorlie等人，2001年）。值得注意的是，BBC与相对较差的无病生存期相关（Rakha等人，2008年）。这种肿瘤亚型的典型特征是雌激素受体、孕激素受体和HER-2的“三阴性”，这意味着大多数BBC不能用现有的靶向治疗（曲妥珠单抗和激素治疗）进行管理（Anders和Carey，2008）。我们实验室和其他人的初步工作已经确定了BBC中的显着分子缺陷，这些缺陷表明DNA修复系统功能失调。例如，我们发现，相对于其他乳腺癌亚型，BBC具有增加数量的低水平DNA拷贝数改变（Bergamaschi et al.，2006年）。此外，我们和其他人已经发现，这种侵袭性癌症亚型与BCRA 1突变的生殖系携带者的肿瘤之间存在基因组变化的BBC模式和许多其他显著的相似性，这些相似性与其他类别的乳腺癌不相同（在Tuner和Reis-Filho，2006中综述）。这些发现特别有趣，因为已知BRCA 1在DNA修复中发挥重要作用，并表明BRCA 1或BRCA 1途径的组分在BBC细胞中存在缺陷。鉴于基底样乳腺癌（BBC）基因组改变的不同模式及其与遗传性BRCA 1突变型肿瘤的相似性，我们假设BBC在DNA修复方面存在潜在缺陷，可能与BRCA 1有关，这可能是治疗上可利用的。该提案的具体目标是（1）表征BBC细胞中的DNA修复缺陷;（2）评估BBC细胞中BRCA 1的表达和功能;（3）识别BBC选择性化学和遗传脆弱性。这项研究旨在更好地了解BBC基因组不稳定性的分子基础，并为目前有限的BBC疗法奠定基础。 与公共卫生的关系：乳腺癌是一种对全世界妇女和一些男子的健康产生深远影响的疾病。最近，强大的分析工具已经确定了一个更有可能导致患者预后不良且治疗选择有限的乳腺癌子集。我们建议研究这种侵袭性乳腺癌亚型的分子特征和可能的治疗方法。

DESCRIPTION (provided by applicant): The National Cancer Institute reports that each year more than 211,000 American women are diagnosed with breast cancer (NCI, 2007). Two crucial components in clinical management of this disease are prediction of patient outcome and treatment response. Recently, expression profiling revealed new and promising classifications of breast cancer, which includes a subtype denoted basal-like breast carcinoma (BBC) (Perou et al., 2000; Sorlie et al., 2001). Notably, BBCs are associated with a comparatively worse disease-free survival (Rakha et al., 2008). This tumor subtype is typified as being "triple-negative" for the estrogen receptor, the progesterone receptor, and HER-2, meaning that the majority of BBCs cannot be managed with existing targeted treatments (trastuzumab and hormonal treatments) (Anders and Carey, 2008). Preliminary work in our lab and by others has identified notable molecular defects in BBCs that are indicative of a dysfunctional DNA repair system. For example, we find that BBCs possess increased numbers of low-level DNA copy-number alterations relative to the other breast cancer subtypes (Bergamaschi et al., 2006). In addition, we and others have found that the BBC pattern of genomic change and numerous other notable similarities exist between this aggressive cancer subtype and the tumors of germline carriers of BCRA1 mutations, similarities not shared with the other classes of breast cancer (reviewed in Tuner and Reis-Filho, 2006). These findings are particularly interesting as BRCA1 is known to play an important role in DNA repair and suggest that BRCA1 or components of the BRCA1 pathway are defective in BBC cells. Given distinct patterns of genomic alteration in basal-like breast carcinomas (BBCs) and their similarity to hereditary BRCA1-mutant tumors, we hypothesize that BBCs have an underlying defect in DNA repair, possibly relating to BRCA1, which might be exploitable therapeutically. The specific aims of this proposal are to (1) characterize DNA repair defects in BBC cells; (2) evaluate expression and function of BRCA1 in BBC cells; and (3) identify BBC-selective chemical and genetic vulnerabilities. This research is intended to provide a better understanding of the molecular underpinnings of BBC genomic instability and lay the foundation for BBC therapies, which are currently limited. PUBLIC HEALTH RELEVANCE: Breast cancer is a disease which has a profound impact on the health of women and some men throughout the world. Recently, powerful analytical tools have identified a subset of breast cancers that are more likely to result in poor patient outcome and for which treatment options are limited. We propose to study the molecular features of and possible therapeutics for this aggressive subtype of breast cancer.