. For women in the United States, epithelial ovarian cancer is the second most common gynecological cancer and a leading cause of death. Women who carry mutations in the BRCA1 gene are at a high risk for development of sporadic ovarian cancers. In these cancers, BRCA1 dysfunction is common, and silencing of genes in the BR(iA1 pathway is apparently involved in their development. BRCA1 and its isoform, BRCA1a, are nuclear-cytoplasm shuttling proteins, tDut the trafficking pathway that is deregulated in ovarian cancers, resulting in cytoplasmic localization of BRCA1, is currently unknown. We have found that wild-type nuclear BRCA1 and BRCA1a proteins inhibit growth of ovarian cancer cells;these proteins bind the nuclear chaperone, Ubc9, and degrade ER-alpha. In contrast, BRCA1/BRCA1a proteins with a cancer-causing C61G mutation or with the Ubc9 binding-site K109R mutation are mis-localized to the cytoplasm and have impaired capacity to inhibit growth of these cells. HYPOTHESIS: Based on these preliminary results, we hypothesize that BRCA1, by binding to Ubc9, functions as a tumor suppressor and thereby inhibits growth of ovarian tumors. For BRCA1 dysfunction, as seen in BRCA1-associated hereditary (genetic) and sporadic ovarian cancers (post-translational modifications), there is disrupted interaction with Ubc9, causing cytoplasmic retention of BRCA1 proteins and deregulated Ubc9 levels, resulting in ovarian cancers.
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