The BARD1 tumor suppressor and breast cancer

描述(申请人提供)：携带BRCA1肿瘤抑制基因胚系突变的女性极易患上基底细胞样乳腺癌，这是一种特别致命的乳腺癌亚型。BRCA1编码的蛋白质在体内与BARD1蛋白以异源二聚体的形式存在，BRCA1的大部分功能，包括其在基因组稳定和肿瘤抑制方面的主要活性，都是由BRCA1/BARD1异源二聚体介导的。事实上，我们之前已经证明，BRCA1或Bard1的乳房特异性失活会引起小鼠肿瘤，与人类BRCA1突变携带者的基底样乳腺癌非常相似。此外，条件性BRCA1和Bard1缺失小鼠的肿瘤在表型上是不可区分的，这表明BRCA1/BARD1异源二聚体介导了这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如何对BRCA1/BARD1异源二聚体的功能做出贡献，这是一个研究不足且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基因的截断胚系突变。虽然这些突变不如涉及BRCA1基因的突变常见，但它们为BRCA1/BARD1介导的肿瘤抑制的分子机制以及BARD1在这一过程中的特定贡献提供了重要线索。有趣的是，与肿瘤相关的BARD1突变特异性地消除了位于BARD1多肽C末端的两个BRCT氨基酸基序中的一个或两个的编码潜力。这些序列被预测以一种磷酸依赖的方式结合蛋白质，因此，通过与其他抑制肿瘤所需的因子相互作用，可能赋予BRCA1/BARD1异源二聚体独特的性质。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异源二聚体的功能，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.