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编码的蛋白与BARD1蛋白以异源二聚体的形式存在于体内，BRCA1的大部分功能，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异源二聚体介导的。事实上，我们之前的研究表明，Brca1或Bard1的乳腺特异性失活引发的小鼠肿瘤与人类Brca1突变携带者的基底样乳腺癌非常相似。此外，条件Brca1-和BARD1 -缺失小鼠的肿瘤在表型上难以区分，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如何促进BRCA1/BARD1异源二聚体的功能，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基因的截断种系突变。尽管与BRCA1基因相关的突变相比，这些突变并不常见，但它们为研究BRCA1/BARD1介导的肿瘤抑制的分子机制以及BARD1在这一过程中的具体作用提供了重要线索。有趣的是，肿瘤相关的BARD1突变特异性地消除了位于BARD1多肽c端的两个BRCT氨基酸基序中的一个或两个的编码潜力。据预测，这些序列以磷酸化依赖的方式结合蛋白质，因此，可能通过与肿瘤抑制所需的其他因子相互作用，赋予BRCA1/BARD1异源二聚体独特的特性。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截断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磷酸化识别。

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.