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.
Women with germline mutations of the BRCA1 tumor suppressor gene are highly predisposed to breast and ovarian cancer. The protein encoded by BRCA1 interacts with BARD1, the protein product of another tumor suppressor gene implicated in hereditary breast and ovarian cancer, and the resulting heterodimeric complex is responsible for the tumor suppressor activities of both proteins. By defining how BRCA1 and BARD1 cooperate in the suppression of breast cancer, the proposed project should identify valuable molecular targets for preventive and therapeutic interventions.
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