Approximately 90% of epithelial ovarian cancers are considered sporadic and they originate from the ovarian surface epithelium. The remaining 5-10% is associated with mutations of BRCA1 gene. There is accumulating evidence to suggest that dysfunction in the BRCA1 pathway may be involved in the pathogenesis of sporadic epithelial ovarian cancer (SEOC). BRCA1 mutations are uncommon in SEOC. Thus there Is strong evidence to suggest that silencing of genes in the BRCA1 pathway (BRCAness) may play a key role in ovarian carcinogenesis. Up regulation of Ubc9 protein levels are seen frequently in ovarian cancers which could be a fundamental part of the neoplastic process. Furthermore, high levels of Ubc9 promote cell invasion and metastasis. We have shown that BRCA1 protein binds to UBC9 and lack of binding resulted in loss of ER-a degradation by BRCA1 proteins in breast cancers. Based on our recent published data we hypothesize that: 1) BRCA1 functions as a tumor suppressor by regulating Ubc9 mediated cellular proliferation of ovarian cancer cells;and 2) Loss of BRCA1 function due to mutations, or post-translational modifications of BRCA1 proteins as seen both in hereditary and sporadic ovarian cancers leads to loss of Ubc9 binding, elevated Ubc9 resulting in ovarian cancers. To test this hypothesis we will study the mechanistic and physiological significance of the interaction between BRCA1 and Ubc9 in different intracellular compartments by altering the binding, endogenous Ubc9 knock down and determining the tumor suppressor activity, nuclear localization by BRCA1 proteins in ovarian cancer cells. We also plan to study the clinical significance of this novel mechanism of tumor suppression by examining the expression of these proteins in clinically annotated human ovarian tissue samples and determining its value as a biomarker platform for early detection, drug screening or clinical end-points. Results from these studies will identify for the first time the underlying molecular mechanism of tumor suppression by BRCA1 in BRCA1-associated familial and sporadic ovarian cancers.
By identifying a novel molecular pathway of tumor suppression that is altered in BRCA1-linked ovarian cancers, this will change the current understanding of how BRCA1 functions as a tumor suppressor. This finding will allow the development of novel biomarkers and functional cell based assay platforms for the rapid discovery of targeted therapies for BRCA1-associated cancers. Because the expression of both Ubc9 and BRCA1 is deregulated in ovarian tumors. BRCA-1-Ubc9 interactions will have implications in ovarian cancers.
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