EVALUATION OF BRCA1/2 MALFUNCTION IN BREAST CANCER

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Abnormalities of several tumor suppressor genes, including BRCA1 and BRCA2, are known to confer susceptibility to human breast cancer. Mutations in the BRCA1 gene have been associated with a majority of familial breast and ovarian cancer. Preliminary studies suggest that mutations in the BRCA2 gene also confer a similar risk of familial breast cancer. However, the frequency of mutation of BRCA1 in non familial breast cancer, which account for 95% of all breast cancer, is reportedly very low. Although mutation of the BRCA1 gene itself may b the crucial event responsible for familial breast cancers, it was recently reported that other mutational events apparently result in functional inactivation of BRCA1 by cytoplasmic mislocation in sporadic breast cancers. Thus, BRCA1 may be a common target in the genesis or progression of the majority of breast cancers. It is the objective of this Phase I proposal to prepare a panel of clinically useful monoclonal antibodies against the BRCA1 and BRCA2 and tumor status using a panel of human breast cancer specimens. These data will support the potential use of BRCA1 and BRCA2 as prognostic markers for primary breast cancer and subsequent investigations pertaining to the molecular mechanism by which alterations of BRCA1 and BRCA2 expression can lead to cancer. PROPOSED COMMERCIAL APPLICATION: Development of clinically useful monoclonal antibodies suitable for immunohistochemical staining of the tumor suppressor genes BRCA1 and BRCA2 might serve as prognostic factors for primary breast cancer, thus establishing a more definitive correlation between tumor status of different evolutionary stages and clinical outcome.