MOLECULAR EPIDEMIOLOGY OF BRCA1 RELATED BREAST NEOPLASIA

描述(申请人描述)：由于隔离乳房 卵巢癌易感基因BRCA1和BRCA2的研究已经完成 对其蛋白质产品的生物功能进行评估， 它们相互作用的细胞途径和分子机制 它们的缺失容易导致乳腺癌和卵巢癌的发展。至 到目前为止，对BRCA1蛋白功能的科学理解仍然 相当有限。事实上，尽管一致的数据表明BRCA1具有功能 与生长抑制和维持基因组稳定有关，许多 关于这种蛋白质的作用的数据仍然存在争议。 可以证实机械学发现的流行病学数据 目前还没有可用的研究。 建议的研究是对合作的分子流行病学比较。 癌基因和肿瘤抑制基因(TSG)在肿瘤中的激活或失活 BRCA1突变携带者的乳腺肿瘤和癌前病变 和非携带者。通过将分子生物学的工具应用于临床 基于调查，分子流行病学研究，这类建议 在这里，启用对疾病机制的间接评估。一元化 在拟议的项目中调查的假设是控制 与BRCA1相同的通路在乳房中的异常频率将会降低 生殖系BRCA1突变携带者的肿瘤高于非携带者。这些基因 在很大程度上独立于BRCA1的通路中的功能将显示 生殖系BRCA1突变的肿瘤中异常率相当 承运人和非承运人。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和 生殖系BRCA1突变携带者和OVT的并发癌前病变 非携带者。申请者将比较异常表情的比率 1)细胞周期调控基因(细胞周期蛋白d1、细胞周期蛋白E、细胞周期蛋白Rb、细胞周期蛋白p53和细胞周期蛋白p21)； 2)携带者组织中的细胞凋亡调控基因(bax-α和bcl2) 和非携带者。在第三个具体目标中，将建立一个统计模型 构建用于鉴定异常癌基因和TSG表达模式的 与每个组(BRCA1突变携带者和 非携带者)和每一种癌前组织学检查。 这些研究的假设与正在进行的工作很好地结合在一起 在项目导师的实验室内并进入项目导师的研究目标 首席调查员。拟议的研究将被用来证实 和/或更直接地评估研究结果的临床意义 机械学研究。拟议中的研究也可能带来新的见解。 转化为疾病机制。这样的洞察力可以通过更多的 直接机械论的研究。从这一事件中得出的机械论的见解 每种类型的研究都将用于Rational的开发 化学预防干预。

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.