It is still unclear how BRCA1 suppresses tumorigenesis 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 Bard1 or Brca1. The common basal-like phenotype shared by the Bard1- and Brca1-mutant mammary carcinomas implies that BRCA1-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 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. In new preliminary data, we have identified a novel ubiquitin-binding protein that is a potent enzymatic inhibitor of the BRCA1/BARD1 heterodimer and we have shown that the E3 ligase activity of BRCA1 is dispensable for mammalian cell viability and certain aspects of BRCA1 function in maintenance of genome stability. To elucidate the molecular mechanisms of BRCA1-mediated tumor suppression, we will now investigate how the BRCA1/BARD1 heterodimer and its associated E3 ligase activity promote tumor suppression and 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) define the role of this E3 ligase activity in DNA repair and cell cycle checkpoint control, and 3) explore the molecular mechanisms of ubiquitin-mediated signaling by BRCA1/BARD1.
The research proposal will evaluate how the BRCA1/BARD1 heterodimer and its associated E3 ubiquitin ligase activity promote tumor suppression and why disruption of BRCA1/BARD1 function leads to formation of basal-like breast cancer. A better understanding of the etiology of basal-like breast cancer will allow for development of improved therapeutic strategies to treat this disease.
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