The BARD1 tumor suppressor and breast cancer

描述（由申请人提供）：携带 BRCA1 肿瘤抑制基因种系突变的女性极易患基底样乳腺癌，这是一种特别致命的乳腺癌亚型。 BRCA1 编码的蛋白在体内以与 BARD1 蛋白的异二聚体形式存在，大多数 BRCA1 功能，包括其在基因组稳定性和肿瘤抑制方面的主要活性，都是由 BRCA1/BARD1 异二聚体介导的。事实上，我们之前表明，Brca1 或 Bard1 的乳腺特异性失活会引发与人类 BRCA1 突变携带者的基底样乳腺癌非常相似的小鼠肿瘤。此外，条件性 Brca1 和 Bard1 缺失小鼠的肿瘤在表型上无法区分，表明 BRCA1/BARD1 异二聚体介导两种蛋白的肿瘤抑制活性。因此，为了了解 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 异二聚体的功能，这是一个尚未得到充分研究且仍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患者中发现了 BARD1 基因的截短种系突变。尽管这些突变不如涉及 BRCA1 基因的突变常见，但它们提供了有关 BRCA1/BARD1 介导的肿瘤抑制的分子机制以及 BARD1 对此过程的具体贡献的重要线索。有趣的是，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 氨基酸基序之一或两者的编码潜力。这些序列预计会以磷酸依赖性方式结合蛋白质，因此可能通过与肿瘤抑制所需的其他因子相互作用而赋予 BRCA1/BARD1 异二聚体独特的特性。因此，为了阐明BRCA1/BARD1促进肿瘤抑制的机制，我们将确定肿瘤相关的截短BARD1突变如何影响BRCA1/BARD1异二聚体的功能以及BARD1的肿瘤抑制活性是否需要BRCT磷酸识别。

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.