MOLECULAR EPIDEMIOLOGY OF BRCA1 RELATED BREAST NEOPLASIA

BRCA1 相关乳腺肿瘤的分子流行病学

• 批准号: 6522394
• 负责人: Anne M Blackwood-Chirchir
• 金额: $ 8.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522394
• 关键词: apoptosis; brca gene; breast neoplasms; cell cycle; cyclins; female; genetic carriers; human data; loss of heterozygosity; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nucleic acid sequence; oncoprotein p21; protooncogene; regulatory gene; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (Applicant's Description): Since the isolation of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, studies have been undertaken to evaluate the biologic functions of their protein products, the cellular pathways with which they interact, and the molecular mechanisms by which their loss predisposes to breast and ovarian cancer development. To date, scientific understanding of the function of the BRCA1 protein remains quite limited. In fact, while consistent data suggest functions for BRCA1 related to growth suppression and the maintenance of genome stability, much of the data about the role of this protein remains controversial. Epidemiologic data that could corroborate the findings of mechanistic studies are not presently available. The proposed study is a molecular epidemiologic comparison of cooperating oncogenes and tumor suppressor genes (TSG) activated or inactivated in the breast tumors and pre-malignant breast lesions of BRCA1 mutation carriers and non-carriers. By bringing the tools of molecular biology to clinically based investigation, molecular epidemiology studies, of the kind proposed here, enable indirect evaluation of disease mechanisms. The unifying hypothesis investigated in the proposed project is that genes that control the same pathways as BRCA1 will less frequently be abnormal in the breast tumors of germline BRCA1 mutation carriers than of non-carriers. Genes that function in pathways that are largely independent of BRCA1 will show abnormalities at comparable rates in the tumors of germline BRCA1 mutation carriers and of non-carriers. In the first two specific aims, immunohistochemical assays will be performed on the tumor samples and concurrent pre-malignant lesions of germline BRCA1 mutation carriers and of non-carriers. The applicants will compare the rates of abnormal expression of: 1) cell cycle control genes (cyclin D1, cyclin E, Rb, p53 and p2l); and 2) apoptosis control genes (Bax-alpha, and BCL-2) in the tissues of carriers and non-carriers. In the third specific aim, a statistical model will be constructed to identify the abnormal oncogene and TSG expression pattern that is associated with each group (BRCA1 mutation carriers and non-carriers) and with each of the pre-malignant histologies. The hypotheses of these studies are well integrated into the ongoing work within the project mentor's laboratory and into the research goals of the principal investigator. The proposed studies will be used to corroborate and/or evaluate the clinical significance of findings from more directly mechanistic studies. The proposed studies may also lead to new insights into disease mechanisms. Such insights can be fully evaluated by more directly mechanistic studies. The mechanistic insights inferred from the studies of each type will be employed in the development of rational chemoprevention interventions.

描述（申请人的描述）：自从隔离乳房以来 和卵巢癌易感基因BRCA1和BRCA2，研究已 旨在评估其蛋白质产品的生物功能， 它们相互作用的细胞途径以及分子机制 它们的缺失会导致乳腺癌和卵巢癌的发生。 到 迄今为止，对 BRCA1 蛋白功能的科学认识仍然存在 相当有限。 事实上，虽然一致的数据表明 BRCA1 具有功能 与生长抑制和基因组稳定性的维持有关，很多 关于这种蛋白质的作用的数据仍然存在争议。 可以证实机制研究结果的流行病学数据 目前还没有研究。 拟议的研究是合作研究的分子流行病学比较 癌基因和肿瘤抑制基因（TSG）在体内激活或失活 BRCA1突变携带者的乳腺肿瘤和癌前病变 和非运营商。 通过将分子生物学工具引入临床 基于调查、分子流行病学研究的建议 在这里，能够间接评估疾病机制。 统一的 拟议项目中研究的假设是控制基因 与 BRCA1 相同的途径在乳房中出现异常的几率较低 种系 BRCA1 突变携带者的肿瘤发生率高于非携带者。 基因 很大程度上独立于 BRCA1 的通路中的功能将显示 种系 BRCA1 突变肿瘤中的异常率相当 运营商和非运营商。 在前两个具体目标中， 将对肿瘤样本进行免疫组织化学分析 种系 BRCA1 突变携带者并发的癌前病变 非携带者。 申请人将比较异常表达率 1) 细胞周期控制基因（细胞周期蛋白 D1、细胞周期蛋白 E、Rb、p53 和 p2l）；和 2）携带者组织中的凋亡控制基因（Bax-α和BCL-2） 和非运营商。 在第三个具体目标中，统计模型将是 构建用于识别异常癌基因和 TSG 表达模式 与每个组相关（BRCA1 突变携带者和 非携带者）和每种恶变前的组织学。 这些研究的假设很好地融入了正在进行的工作 在项目导师的实验室内并进入研究目标 首席研究员。 拟议的研究将用于证实 和/或更直接地评估研究结果的临床意义 机理研究。 拟议的研究也可能带来新的见解 进入疾病机制。 这些见解可以通过更多的人来充分评估 直接机理研究。 从机制中推断出的见解 每种类型的研究都将用于合理发展 化学预防干预措施。