The BARD1 tumor suppressor and breast cancer

BARD1肿瘤抑制因子和乳腺癌

• 批准号: 9045581
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045581
• 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; 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BRCA 1肿瘤抑制基因生殖系突变的女性高度易患基底样乳腺癌，这是一种特别致命的乳腺癌亚型。由BRCA 1编码的蛋白质在体内作为与BARD 1蛋白的异源二聚体存在，并且大多数BRCA 1功能，包括其在基因组稳定性和肿瘤抑制中的主要活性，由BRCA 1/BARD 1异源二聚体介导。事实上，我们以前表明，乳腺特异性失活的Brca 1或Bard 1 eliminate小鼠肿瘤，非常类似于基底样乳腺癌的人类BRCA 1突变携带者。此外，条件性Brca 1和Bard 1基因敲除小鼠的肿瘤在表型上是不可区分的，这表明BRCA 1/BARD 1异源二聚体介导了两种蛋白质的肿瘤抑制活性。因此，为了了解BRCA 1抑制乳腺癌和卵巢癌的机制，有必要阐明BARD 1如何促进BRCA 1/BARD 1异源二聚体的功能，这是一个尚未充分研究且仍知之甚少的关键问题。最近，在非BRCA 1/2家族性乳腺癌和卵巢癌患者中发现了BARD 1基因的截短生殖系突变。尽管这些突变比BRCA 1基因的突变不常见，但它们为BRCA 1/BARD 1介导的肿瘤抑制的分子机制以及BARD 1对这一过程的具体贡献提供了重要线索。有趣的是，肿瘤相关的BARD 1突变特异性地消除了位于BARD 1多肽C末端的两个BRCT氨基酸基序中的一个或两个的编码潜力。预测这些序列以磷酸依赖性方式结合蛋白质，因此，可以通过与肿瘤抑制所需的其他因子相互作用而赋予BRCA 1/BARD 1异源二聚体独特的性质。因此，为了阐明BRCA 1/BARD 1促进肿瘤抑制的机制，我们将确定肿瘤相关的截短BARD 1突变如何影响BRCA 1/BARD 1异二聚体的功能，以及BARD 1的肿瘤抑制活性是否需要BRCT磷酸识别。