The BARD1 tumor suppressor and breast cancer

BARD1肿瘤抑制因子和乳腺癌

• 批准号: 8835070
• 负责人: RICHARD J BAER
• 金额: $ 33.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835070
• 关键词: Affect; Amino Acid Motifs; Animal Model; BARD1 gene; BRCA1 Mutation; BRCA1 gene; Binding Proteins; Biological; Breast Carcinoma; C-terminal; Code; Complex; Genome Stability; Germ-Line Mutation; Hereditary Breast Carcinoma; Housekeeping; Human; Knock-in Mouse; Knockout Mice; Malignant neoplasm of ovary; Mammary gland; Mediating; Missense Mutation; Modeling; Molecular; Molecular Target; Mus; Mutation; N-terminal; Nature; Nuclear; Patients; Preventive Intervention; Process; Property; Proteins; Proteomics; Role; Testing; Therapeutic Intervention; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Woman; clinically relevant; in vivo; malignant breast neoplasm; mouse model; mutant; mutation carrier; polypeptide; public health relevance; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Women who carry germline mutations of the BRCA1 tumor suppressor gene are highly predisposed to basal- like breast carcinoma, an especially lethal subtype of breast cancer. The protein encoded by BRCA1 exists in vivo as a heterodimer with the BARD1 protein, and most BRCA1 functions, including its major activities in genome stability and tumor suppression, are mediated by the BRCA1/BARD1 heterodimer. Indeed, we previously showed that mammary-specific inactivation of either Brca1 or Bard1 elicits murine tumors that closely resemble the basal-like breast cancers of human BRCA1 mutation carriers. Furthermore, the tumors of conditional Brca1- and Bard1-null mice are phenotypically indistinguishable, suggesting that the BRCA1/BARD1 heterodimer mediates the tumor suppression activity of both proteins. Therefore, to understand the mechanisms by which BRCA1 suppresses breast and ovarian cancer, it will be necessary to elucidate how BARD1 contributes to the function of the BRCA1/BARD1 heterodimer, a critical issue that has been understudied and remains poorly understood. Recently, truncating germline mutations of the BARD1 gene were identified in patients with non-BRCA1/2 familial breast and ovarian cancer. Although less common than those involving the BRCA1 gene, these mutations provide important clues regarding the molecular mechanisms of BRCA1/BARD1-mediated tumor suppression, as well as the specific contribution of BARD1 to this process. Interestingly, the tumor-associated BARD1 mutations specifically eliminate the coding potential for one or both of the two BRCT amino acid motifs that lie at the C-terminus of the BARD1 polypeptide. These sequences are predicted to bind proteins in a phospho-dependent manner and, as such, may confer unique properties to the BRCA1/BARD1 heterodimer by interacting with other factors required for tumor suppression. Therefore, to elucidate the mechanisms by which BRCA1/BARD1 promotes tumor suppression, we will determine how tumor-associated truncating BARD1 mutations affect the functions of the BRCA1/BARD1 heterodimer and whether BRCT phospho-recognition is required for the tumor suppression activity of BARD1.

描述（由申请人提供）：携带BRCA1肿瘤基因种系突变的女性高度倾向于基础乳腺癌，这是乳腺癌的尤其是致命的亚型。由BRCA1编码的蛋白质存在于体内作为与Bard1蛋白的异二聚体，大多数BRCA1功能（包括其在基因组稳定性和肿瘤抑制中的主要活性）都是由BRCA1/BARD1异二聚体介导的。确实，我们先前表明，BRCA1或BARD1的乳腺特异性灭活引起了鼠肿瘤，它们与人BRCA1突变载体的基底样乳腺癌非常相似。此外，有条件的BRCA1和BARD1-NULL小鼠的肿瘤在表型上是无法区分的，这表明BRCA1/BARD1异二聚体介导了两种蛋白质的肿瘤抑制活性。因此，要了解BRCA1抑制乳腺癌和卵巢癌的机制，有必要阐明Bard1如何促进BRCA1/BARD1 HETRODIMER的功能，这是一项研究且仍然知之甚少的关键问题。最近，在非BRCA1/2家族性乳腺癌和卵巢癌的患者中鉴定出Bard1基因的截短种系突变。尽管这些突变不如涉及BRCA1基因的基因涉及BRCA1基因，但对于BRCA1/BARD1介导的肿瘤抑制的分子机制提供了重要的线索，以及BARD1对此过程的特定贡献。有趣的是，与肿瘤相关的Bard1突变特异性消除了位于Bard1多肽C末端的两个BRCT氨基酸基序中的一个或两个。这些序列被预测会以磷酸依赖性的方式结合蛋白质，因此，通过与抑制肿瘤抑制所需的其他因素相互作用，可以将独特的特性赋予BRCA1/BARD1异二聚体。因此，为了阐明BRCA1/BARD1促进肿瘤抑制的机制，我们将确定与肿瘤相关的截短BARD1突变如何影响BRCA1/BARD1 HETRODIMER的功能，以及BRCT磷酸化的肿瘤抑制Bard1的肿瘤抑制活性是否需要BRCT磷酸化。