Role of BRCA1 as a Human Tumor Suppressor Gene

描述(由申请人提供)： 背景：乳腺癌易感基因-1(BRCA1)的遗传突变是乳腺癌、卵巢癌和其他肿瘤类型的高危因素。越来越多的证据表明，BRCA1的下调或功能失活在散发性(非遗传性)癌症的发展中发挥了作用。BRCA1在细胞周期进程和DNA修复中起着调节作用。然而，这些作用的分子基础尚不清楚，也不知道BRCA1是否在癌症抑制中发挥其他功能。 初步研究：在最初的资助期间，我们在了解BRCA1的分子作用方面取得了很大进展。我们确定了BRCA1在调节端粒酶和端粒长度和稳定性方面的作用。我们还展示了BRCA1在调节热休克反应和一种小的热休克蛋白HSP27的表达中的作用。我们开发了小干扰RNA来非毒性地耗尽BRCA1，使我们能够研究内源BRCA1的生物学功能。我们使用DNA微阵列分析来识别BRCA1调节的新基因，包括参与抗氧化反应的基因；我们记录了BRCA1在保护细胞免受氧化应激中的功能作用。 假设：BRCA1通过几种不同的机制来维持基因组和蛋白质组的完整性，这些机制在共同点上趋同：1)稳定端粒；2)刺激抗氧化防御。相反，这些功能的丧失会促进基因组/蛋白质组的不稳定，导致肿瘤的发生。 研究目的：本项目的主要目标是：SA1。目的：阐明BRCA1在TERT调控和端粒维持中的作用；评估BRCA1在培养细胞中保护细胞免受氧化应激的机制(S)；以及SA3。在实验动物模型中对BRCA1在体内抗氧化反应中的作用进行生理学验证性研究。 意义：这一竞争延续的焦点是进一步阐明BRCA1的分子功能，特别是在乳腺上皮细胞类型中。利用在最初阶段获得的见解，我们将扩展我们对BRCA1抑瘤活性的分子基础的了解。BRCA1在端粒调节和抗氧化反应中的作用也对衰老研究有意义。人们希望从这些研究中获得的知识将导致癌症控制和治疗的新方法。

DESCRIPTION (provided by applicant): Background: Inherited mutations of the breast cancer susceptibility gene-1 (BRCA1) confer a high risk for breast cancer, ovarian cancer, and other tumor types. Accumulating evidence suggests that down-regulation or functional inactivation of BRCA1 plays a role in the development of sporadic (non-hereditary) cancers. BRCA1 plays roles in the regulation of cell cycle progression and DNA repair. However, the molecular bases for these roles are unclear, nor is it known if BRCA1 exerts other functions in cancer suppression. Preliminary Studies: During the initial grant period, we made great progress in understanding the molecular actions of BRCA1. We identified roles for BRCA1 in regulating the telomerase enzyme and telomere length and stability. We also demonstrated a role for BRCA1 in regulating the heat shock response and expression of a small heat shock protein, HSP27. We developed small interfering RNAs to non-toxically deplete BRCA1, allowing us to study the biological functions of endogenous BRCA1. We used DNA microarray analyses to identify novel BRCA1-regulated genes, including genes implicated in the antioxidant response; and we documented functional roles for BRCA1 in protecting cells against oxidative stress. Hypothesis: BRCA1 functions to preserve genomic and proteomic integrity via several distinct mechanisms that converge at common points: 1) stabilization of telomeres; and 2) stimulating antioxidant defenses. Conversely, loss of these functions promotes genomic/proteomic instability, leading to tumorigenesis. Research Aims: The major goals of this project are: SA1. To delineate the roles of BRCA1 in TERT regulation and telomere maintenance; SA2. To assess the mechanism(s) by which BRCA1 protects cells against oxidative stress in cultured cells; and SA3. To perform physiologic confirmatory studies on the role of BRCA1 in the antioxidant response in vivo in an experimental animal model. Significance: The focus of this competing continuation is to further elucidate the molecular function of BRCA1, particularly in mammary epithelial cell types. Using insights gained during the initial period, we will extend our knowledge of the molecular basis of the tumor suppressor activity of BRCA1. The roles of BRCA1 in telomere regulation and the antioxidant response also have implications for aging research. It is hoped that knowledge gained from these studies will lead to new approaches to cancer control and treatment.