BRCA1 GENE GENE PRODUCT Mutation in breast carcinoma (BRCA) 1 gene, a newly discovered member of the tumor suppressor genes is found in about two-thirds of heritable breast carcinomas and in an unestimated number of ovarian cancers. As reported in the March issue of Nature Genetics, the gene encodes a 190-kDa secretory protein. The protein contains a short sequence shared by granins, proteins in various types of secretory vesicles whose functions is not yet clear. In contrast to the prevailing idea that the BRCA1 gene product may be a transcription factor and thus may reside in the nuclei of cells, the protein was found in the cytoplasm of cells. Chen et al reported in Science (Volume 270, 789, 1995) that BRCA1 protein was found almost exclusively in the cytoplasm of breast and ovarian cancer cell lines. However, the BRCA1 was present in the nuclei of many other human cells. In Western blot analysis, two different polyclonal antibodies reacted with a 220 kD protein. The authors transfected cells with a vector that contained BRCA1 cDNA in-frame with a Flag-terminal region. The tagged protein was found in the nuclei of transfected normal human breast epithelial cells and fibroblasts. However, several human breast cancer cell lines such as T47D and MD468 exhibited the tagged protein in the cytoplasm. In contrast to these findings, Scully et al reported in the April 5, 1996 issue of Science that by using an affinity purified antibody with established specificity to the BRCA1 protein, they were only able to demonstrate a nuclear staining for the protein. Regardless of the tissue of origin, a dot pattern of nuclear staining was observed in the nuclei of all human cell lines that were examined. However, the antibody gave a cytoplasmic staining in primary human mammary epithelial cells. Also, when monoclonal antibody to the BRCA1 protein was used, a weak cytoplasmic staining was observed in certain breast and ovarian carcinoma cell lines. When a different fixative was used (alcoholic formalin) and tissues were embedded in paraffin, the pattern of staining changed. In a variety of tumor cell lines, the location of the signal varied from a predominantly nuclear to mainly cytoplasmic to both cytoplasmic and nuclear stainings. In view of these results, the authors suggested that it can not be concluded that wild type BRCA1 is specifically excluded from the nuclei of sporadic breast and ovarian cancer cell lines. Since the localization of the BRCA1 protein seems to differ based on the antibody and the method of fixation that is being used, the true intracellular localization of the protein remains to be shown. If the presence of secreted protein can be confirmed, a receptor may exist for this gene product. It is conceivable that mutation in such a receptor may account for some breast and ovarian cancers. In addition, such a receptor may become the appropriate target for anti-cancer drugs. Database Links: Gene Map Locus: 17q21