The Role of BRCA1/BARD1 in Basal-Like Breast Cancer

目前还不清楚BRCA 1是如何抑制正常乳腺上皮细胞中的肿瘤发生的，以及BRCA 1 突变携带者发展为基底样乳腺癌。在体内，BRCA 1以异二聚体的形式存在， BARD 1蛋白及其许多生物学特性是通过BRCA 1/BARD 1复合物介导的。 我们最近使用条件突变来显示基底样乳腺癌可以在小鼠中诱发 通过Bardl或Brcal的乳腺特异性失活。共同的基底样表型共享的 Bardl-和Brcal-突变乳腺癌意味着BRC A1介导的肿瘤抑制是一种免疫抑制剂。 由BRCA 1/BARD 1异二聚体实现。与此同时，生物化学研究表明， 异二聚体是一种有效的泛素E3连接酶。此外，我们发现BRCA 1/BARD 1诱导了 形成K6连接的多聚泛素链，其在结构上不同于常规的K48连接的多聚泛素链。 链标记细胞蛋白质的蛋白酶体降解，最近的研究表明，蛋白质 携带K6连接的链不被作为周转的目标。此外，由于BRC A1/BARD 1的E3活性 被肿瘤相关的BRCA 1错义突变消除，异二聚体的酶功能被 可能对肿瘤抑制至关重要。因此，为了阐明BRCA 1- 我们将评估BRCA 1/BARD 1异二聚体及其相关的E3 连接酶活性促进肿瘤抑制并研究为什么BRCA 1/BARD 1功能破坏导致 基底样乳腺癌的形成。特别地，我们将1）确定是否E3连接酶的活性， BRCA 1/BARD 1是正常发育和BRCA 1介导的肿瘤抑制所必需的，2）检查 这种E3连接酶活性在双链DNA断裂修复和细胞周期检查点控制中作用，3） 探索BRCA 1/BARD 1介导的泛素信号传导的分子机制，以及4）检查 BRCA 1和PTEN通路在基底样乳腺癌发展中的相互作用。

It is still unclear how BRCA1 suppresses rumorigenesis in normal mammary epithelial cells and why BRCA1 mutation carriers develop basal-like breast carcinomas. In vivo, BRCA1 exists as a heterodimer with the BARD1 protein, and many of its biological properties are mediated through the BRCA1/BARD1 complex. We recently used conditional mutagenesis to show that basal-like breast carcinomas can be induced in mice by mammary-specific inactivation of either Bardl or Brcal. The common basal-like phenotype shared by the Bardl- and Brcal-mutant mammary carcinomas implies that BRC A1-mediated tumor suppression is implemented by the BRCA1/BARD1 heterodimer. Meanwhile, biochemical studies have show that the heterodimer is a potent ubiquitin E3 ligase. Moreover, we have found that BRCA1/BARD1 induces the formation of K6-linked polyubiquitin chains that are structurally distinct from the conventional K48-linked chains that mark cellular proteins for proteasomal degradation, and recent studies indicate that proteins bearing K6-linked chains are not targeted for turnover. Furthermore, since the E3 activity of BRC A1/BARD 1 is ablated by tumor-associated BRCA1 missense mutations, the enzymatic function of the heterodimer is likely to be essential for tumor suppression. Thus, to elucidate the molecular mechanisms of BRCA1- mediated tumor suppression, we will evaluate how the BRCA1/BARD1 heterodimer and its associated E3 ligase activity promote tumor suppression and investigate why disruption of BRCA1/BARD1 function leads to formation of basal-like breast cancer. In particular, we will 1) determine whether the E3 ligase activity of BRCA1/BARD1 is required for normal development and BRCA1-mediated tumor suppression, 2) examine the role of this E3 ligase activity in double-strand DNA break repair and cell cycle checkpoint control, 3) explore the molecular mechanisms of ubiquitin-mediated signaling by BRCA1 /BARD 1, and 4) examine interactions between the BRCA1 and PTEN pathways in the development of basal-like breast cancer.