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.
Germline mutations of the BRCA1 gene are a major cause of familial breast cancer, and women bearing these lesions face a extraordinary lifetime risk (>80%) of developing breast cancer. Moreover, most of the tumors that are arise in BRCA1 mutation carriers display the basal-like phenotype, and thus fall within the clinical subgroup of breast cancer associated with the poorest prognosis.
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