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(申请人提供)：目前仍不清楚BRCA1如何抑制正常乳腺上皮细胞的肿瘤形成，以及为什么BRCA1突变携带者会发展为基底样癌。在体内，BRCA1与BARD1蛋白以异源二聚体的形式存在，其许多生物学特性是通过BRCA1/BARD1复合体介导的。我们最近使用条件突变来证明，可以通过乳腺特异性Bard1或BRCA1的失活在小鼠中诱导基底样乳腺癌。Bard1和BRCA1突变乳腺癌共有的共同的碱基样表型意味着BRCA1介导的肿瘤抑制是通过BRCA1/BARD1异源二聚体实现的。同时，生化研究表明，异源二聚体是一种有效的泛素E3连接酶。此外，我们发现BRCA1/BARD1诱导K6连接的多泛素链的形成，这些多泛素链在结构上与传统的K48连接的链不同，K48连接的链标记细胞蛋白质的蛋白酶体降解。在新的初步数据中，我们发现了一种新的泛素结合蛋白，它是BRCA1/BARD1异源二聚体的有效酶抑制因子，我们已经证明BRCA1的E3连接酶活性对于哺乳动物细胞的生存和BRCA1在维持基因组稳定性方面的某些方面是必不可少的。为了阐明BRCA1介导的肿瘤抑制的分子机制，我们现在将研究BRCA1/BARD1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BRCA1/BARD1功能中断会导致基底样乳腺癌的形成。特别是，我们将1)确定BRCA1/BARD1的E3连接酶活性是否是正常发育和BRCA1介导的肿瘤抑制所必需的；2)确定该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BRCA1/BARD1介导的泛素信号转导的分子机制。公共卫生相关性：该研究计划将评估BRCA1/BARD1异源二聚体及其相关的E3泛素连接酶活性如何促进肿瘤抑制，以及为什么BRCA1/BARD1功能中断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有助于开发改进的治疗策略来治疗这种疾病。