The Role of BRCA1/BARD1 in Basal-like Breast Cancer

BRCA1/BARD1 在基底样乳腺癌中的作用

• 批准号: 7738219
• 负责人: RICHARD J BAER
• 金额: $ 33.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738219
• 关键词: Animals; BARD1 gene; BRCA1 Mutation; BRCA1 gene; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Breast Carcinoma; Cell Cycle Checkpoint; Cell Survival; Cell physiology; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Development; Disease; Embryo; Epithelial Cells; Etiology; Gene Targeting; Genome Stability; Germ-Line Mutation; Hereditary Breast Carcinoma; Knock-in Mouse; Knockout Mice; Link; Maintenance; Mammalian Cell; Mammary gland; Mediating; Missense Mutation; Mitotic; Molecular; Mus; Mutagenesis; Pathway interactions; Phase; Phenotype; Polyubiquitin; Property; Proteins; Research Proposals; Role; Signal Transduction; System; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; mutant; mutant mouse model; mutation carrier; novel; null mutation; public health relevance; repaired; response; tumor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): It is still unclear how BRCA1 suppresses tumorigenesis in normal mammary epithelial cells and why BRCA1 mutation carriers develop basal-like breast carcinomas. In vivo, BRCA1 exists as a heterodimer with the BARD1 protein, and many of its biological properties are mediated through the BRCA1/BARD1 complex. We recently used conditional mutagenesis to show that basal-like breast carcinomas can be induced in mice by mammary-specific inactivation of either Bard1 or Brca1. The common basal-like phenotype shared by the Bard1- and Brca1-mutant mammary carcinomas implies that BRCA1-mediated tumor suppression is implemented by the BRCA1/BARD1 heterodimer. Meanwhile, biochemical studies have show that the heterodimer is a potent ubiquitin E3 ligase. Moreover, we found that BRCA1/BARD1 induces the formation of K6-linked polyubiquitin chains that are structurally distinct from the conventional K48-linked chains that mark cellular proteins for proteasomal degradation. In new preliminary data, we have identified a novel ubiquitin-binding protein that is a potent enzymatic inhibitor of the BRCA1/BARD1 heterodimer and we have shown that the E3 ligase activity of BRCA1 is dispensable for mammalian cell viability and certain aspects of BRCA1 function in maintenance of genome stability. To elucidate the molecular mechanisms of BRCA1-mediated tumor suppression, we will now investigate how the BRCA1/BARD1 heterodimer and its associated E3 ligase activity promote tumor suppression and why disruption of BRCA1/BARD1 function leads to formation of basal- like breast cancer. In particular, we will 1) determine whether the E3 ligase activity of BRCA1/BARD1 is required for normal development and BRCA1-mediated tumor suppression, 2) define the role of this E3 ligase activity in DNA repair and cell cycle checkpoint control, and 3) explore the molecular mechanisms of ubiquitin-mediated signaling by BRCA1/BARD1. PUBLIC HEALTH RELEVANCE: The research proposal will evaluate how the BRCA1/BARD1 heterodimer and its associated E3 ubiquitin ligase activity promote tumor suppression and why disruption of BRCA1/BARD1 function leads to formation of basal-like breast cancer. A better understanding of the etiology of basal-like breast cancer will allow for development of improved therapeutic strategies to treat this disease.

描述（由申请人提供）：目前尚不清楚BRCA 1如何抑制正常乳腺上皮细胞中的肿瘤发生，以及BRCA 1突变携带者为何会发生基底样乳腺癌。在体内，BRCA 1与BARD 1蛋白以异源二聚体的形式存在，其许多生物学特性是通过BRCA 1/BARD 1复合物介导的。我们最近使用的条件突变显示，基底样乳腺癌可以诱导小鼠乳腺特异性失活的Bard 1或Brca 1。Bard 1和Brca 1突变型乳腺癌共有的共同基底样表型意味着BRCA 1介导的肿瘤抑制是由BRCA 1/BARD 1异源二聚体实现的。同时，生物化学研究表明，异二聚体是一种有效的泛素E3连接酶。此外，我们发现BRCA 1/BARD 1诱导K6连接的多聚泛素链的形成，该链在结构上不同于标记蛋白酶体降解的细胞蛋白的常规K48连接的链。在新的初步数据中，我们已经确定了一种新的泛素结合蛋白，它是BRCA 1/BARD 1异源二聚体的有效酶抑制剂，我们已经表明，BRCA 1的E3连接酶活性对哺乳动物细胞活力和BRCA 1在维持基因组稳定性方面的某些功能至关重要。为了阐明BRCA 1介导的肿瘤抑制的分子机制，我们现在将研究BRCA 1/BARD 1异源二聚体及其相关的E3连接酶活性如何促进肿瘤抑制，以及为什么BRCA 1/BARD 1功能的破坏会导致基底样乳腺癌的形成。特别是，我们将1）确定BRCA 1/BARD 1的E3连接酶活性是否是正常发育和BRCA 1介导的肿瘤抑制所必需的，2）确定E3连接酶活性在DNA修复和细胞周期检查点控制中的作用，3）探索BRCA 1/BARD 1介导的泛素信号传导的分子机制。公共卫生关系：该研究计划将评估BRCA 1/BARD 1异二聚体及其相关的E3泛素连接酶活性如何促进肿瘤抑制，以及为什么BRCA 1/BARD 1功能的破坏会导致基底样乳腺癌的形成。更好地了解基底细胞样乳腺癌的病因，将允许开发改进的治疗策略来治疗这种疾病。