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overview ONGOING RESEARCH Principal Investigator: Veena N Rao Molecular and Functional Dissection of ELK-1 and BRCA1 tumor suppressor genes in breast, ovarian and prostate cancers. One of the ongoing projects in my lab is centered on ELK-1 which is a member of the ETS super family of genes (ETS-1, ETS-2, ERG, TEL, PEA3, Fli-1, Elk-1, SAP1, etc.) which we have identified, cloned, characterized their functions and studied their role in leukemia's, lymphomas, and sarcomas. Deregulation and mutations of ETS proteins are predominantly found in human cancers. The defective functioning of this signaling network is the root cause of widespread diseases such as cancer. ELK-1 thus forms a central integration point for both growth as well as stress signals and plays a major role in cell proliferation, apoptosis, tumorigenesis, as well as differentiation. We have found the Elk-1 gene product to bind BRCA1 suppress growth and induce apoptosis of human breast and prostate cancer cells. We plan to study the molecular mechanism of growth inhibition and cell death induced by ELK-1 in cancer cells. The second project in my lab since 1994 has been on the Breast and Ovarian cancer susceptibility gene BRCA1. BRCA1 mutations predispose women to breast and ovarian cancers and men to increased risks for prostate cancers. Women with BRCA1 mutations are estrogen receptor –negative, progesterone receptor-negative and HER-2 receptor –negative (Triple Negative breast cancers). TNBC are highly aggressive, more common in young African American women and Hispanic women, have higher rates of distant metastasis and currently there are no targeted treatments against these cancers. There is significant overlap between TNBC and BRCA1 associated breast cancers which suggests that dysfunction in the BRCA1 pathway may be responsible for the development of these cancers. We have discovered two short forms of BRCA1 proteins named BRCA1a and BRCA1b which are expressed at reduced levels in breast and ovarian cancers and are also localized in the mitochondria. Recently we demonstrated for the first time using a gene therapy strategy that introducing BRCA1a protein into TNBC, hormone independent ovarian and prostate cancers induces cell death and stops tumor development. There was a national press release on this work. This major finding will provide new therapies in the future for the treatment of one of the biggest needs in TNBC, ovarian and prostate cancer research. We have recently found SUMO-E2-conjugating enzyme Ubc9 to be a new binding partner for BRCA1 proteins. Mutation in the Ubc9 binding site as well as BRCA1 cancer-predisposing mutation disrupted the ability to both bind as well as modulate ER-alpha transcriptional activity in breast cancer cells. BRCA1 thus belongs to a family of RING-finger Sumo-1 and Ubc9-dependent E3 Ubiquitin ligase that induce turnover of estrogen receptor following its sumoylation and disruption of this pathway in women with BRCA1 mutations can result in TNBC. There are currently no targeted treatments against TNBC. The results that will be obtained from these studies will uncover the paradox as to why BRCA1 dysfunction leads to estrogen receptor positive and triple negative breast cancers as well as develop single cell based assays that can be used to identify functionally relevant BRCA1 mutations that can validate their risk for developing aggressive breast cancers as well as design targeted small molecules that can mimic the function of BRCA1 to treat these TNBC. The implications of this study in Cancer health disparities are immense. We have filed several patents on this work.
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