Most cases of hereditary breast cancer can be attributed to germline mutations in either the BRCA1 or BRCA2 tumor suppressor gene. Although these genes do not share sequence homology, their protein products interact in vivo to form stable nuclear complexes. Thus, defects in a common biochemical pathway involving BRCA1 and BRCA2 may be responsible for most cases of familial breast cancer. When cells are subjected to genotoxic stress, the BRCA1/2 complexes are rapidly mobilized to sites of DNA damage. While this and other observations suggest a role for these proteins in maintaining genomic stability, the precise molecular functions of BRCA1 and BRCA2 have not been defined, and the mechanisms by which they suppress tumor formation are not understood.

To address these issues, we are characterizing BRCA1/BRCA2 protein complexes and evaluating their biological functions. These studies have led to the isolation of several novel factors that interact with BRCA1 in vivo, including the BRCA1-associated RING domain (BARD1) protein. BARD1 is structurally related to BRCA1, and pilot studies have shown that its gene also serves as a target of tumorigenic mutations in rare cases of hereditary breast cancer. Moreover, since the interaction between these proteins is specifically ablated by tumor-associated BRCA1 mutations, BARD1 appears to be required for BRCA1-mediated tumor suppression. Further studies are required to understand why germline mutations of BRCA1/2 predispose women to breast cancer.

Selected Publications:

• Wu, L.C., Wang, Z.W., Tsan, J.T., Spillman, M.A., Phung, A., Xu, X.L., Yang, M.-C.W., Hwang, L.-Y., Bowcock, A.M., Baer, R. (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genetics 14: 430-440.
• Jin, Y., Xu, X.L., Yang, M.-C.W., Wei, F., Ayi, T.C., Bowcock, A.M., and Baer, R. (1997) Cell cycle-dependent colocalization of BARD1 and BRCA1 in discrete nuclear domains. Proc. Natl. Acad. Sci. USA, 94: 12075-12080.
• Thai, T.H., Du, F., Tsan, J.T., Jin, Y., Phung, A., Spillman, M.A., Massa, H.F., Muller, C.Y., Ashfaq, R., Mathis, J.M., Miller, D.S., Trask, B.J., Baer, R., and Bowcock, A.M. (1998) Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian, and uterine cancers. Hum. Mol. Genet. 7: 195-202.

Yu, X., Wu, L.C., Bowcock, A.M., Aronheim, A., and Baer, R. (1998) The carboxy-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273: 25,388-25,392.

[Go to top of Document]