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

侵袭性基底样乳腺癌基因组不稳定性的分子基础

• 批准号: 8194822
• 负责人: Ilona Noelani Holcomb
• 金额: $ 5.3万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-05-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8194822
• 关键词: American; BRCA1 gene; Biological Assay; Biological Models; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Cell Line; Cell Survival; Cells; Characteristics; Chemicals; Classification; Clinical Management; Collection; DNA Damage; DNA Repair; DNA Repair Pathway; DNA copy number; Defect; Diagnosis; Disease; Disease-Free Survival; Drug Delivery Systems; ERBB2 gene; Estrogen receptor negative; Exposure to; Foundations; Genetic; Genetic Predisposition to Disease; Genomic Instability; Genomics; Hormonal; Immunofluorescence Immunologic; Inherited; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Molecular; Molecular Profiling; Motivation; Mutation; National Cancer Institute; Nonhomologous DNA End Joining; Outcome; Pathway interactions; Patients; Pattern; Play; Progesterone Receptors; Proteins; Relative (related person); Reporter; Reporting; Research; Role; System; Testing; Therapeutic; Transcript; Transfection; Trastuzumab; Tumor Subtype; Western Blotting; Woman; Women' s Health; Work; analytical tool; base; cellular targeting; chemical genetics; drug sensitivity; homologous recombination; interest; malignant breast neoplasm; member; men; mutant; neoplastic cell; public health relevance; repaired; response; small hairpin RNA; treatment response; tumor

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.

描述(由申请人提供)：国家癌症研究所报告说，每年有超过211,000名美国妇女被诊断出患有乳腺癌(NCI，2007)。在这种疾病的临床治疗中，两个关键的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，其中包括一种被表示为基底细胞样乳腺癌(BBC)的亚型(Perou等人，2000；Sorlie等人，2001)。值得注意的是，BBC与相对较差的无病存活率有关(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“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)来管理(Anders和Carey，2008)。我们实验室和其他实验室的初步工作已经在血细胞中发现了显着的分子缺陷，这表明DNA修复系统功能失调。例如，我们发现BBC相对于其他乳腺癌亚型具有更多的低水平DNA拷贝数改变(Bergamaschi等人，2006年)。此外，我们和其他人发现，在这种侵袭性癌症亚型和携带BCRA1突变的生殖系携带者的肿瘤之间存在着BBC基因组变化模式和许多其他显著的相似之处，而这些相似之处与其他类型的乳腺癌不同(在Tuner和Reis-Filho，2006年回顾)。这些发现特别有趣，因为已知BRCA1在DNA修复中发挥重要作用，并表明BRCA1或BRCA1途径的组件在BBC细胞中存在缺陷。鉴于基底细胞样乳腺癌(BBC)基因组改变的不同模式以及它们与遗传性BRCA1突变肿瘤的相似性，我们假设BBC在DNA修复方面存在潜在的缺陷，可能与BRCA1有关，这可能是可用于治疗的。该建议的具体目的是(1)表征BBC细胞中的DNA修复缺陷；(2)评估BRCA1在BBC细胞中的表达和功能；以及(3)识别BBC选择性的化学和遗传脆弱性。这项研究旨在更好地了解BBC基因组不稳定的分子基础，并为目前有限的BBC疗法奠定基础。 公共卫生相关性：乳腺癌是一种对世界各地妇女和一些男子的健康有深远影响的疾病。最近，强大的分析工具已经确定了乳腺癌的一部分，这些乳腺癌更有可能导致患者预后不佳，而且治疗选择有限。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。