|Contact Information |
Phone: (404) 489-9993
Fax: (404) 489-9220
MS, Osmania University, India
Ph.D., Osmania University, India; University of Edinburgh, Scotland; Max Planck Institute,
Germany; Massachusetts Institute of Technology, Boston
Postdoc, University of California, Berkeley, CA
Postdoc, Yale University School of Medicine, New Haven, CT
MD, National Cancer Institute, Fredrick, Forgarty Scholar.
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 belongs to the ETS-domain family of ternary complex factors (TCF) which is a major nuclear target for the RAS-MAPK/ERK, SAPK/JNK and p38MAPK stress activated kinases. In the nucleus ELK-1 forms a ternary complex with the serum response factor and the serum response element present in several early growth response genes like c-Fos, Egr-1, Egr-2, and Pip92 etc. 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 focused 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). TN breast cancers 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 TN breast cancers 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. We were the first to show that inhibition of expression of these proteins in normal cells results in cancer and high level of expression of which results in cell death and growth inhibition of TN breast cancers, ovarian and prostate cancers. Recently we demonstrated for the first time using a gene therapy strategy that introducing BRCA1a protein into Triple negative breast cancers, hormone independent ovarian and prostate cancers 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 TN breast cancer, ovarian and prostate cancer research. Our future efforts will be directed towards reducing the cancer disparities among minority populations by BRCA1 gene therapy using proteomics based sophisticated nano technologies. We have recently found SUMO-E2-conjugating enzyme Ubc9 to be a new binding partner for BRCA1, BRCA1a and BRCA1b proteins. Mutation in the Ubc9 binding site as well as BRCA1 RING domain cancer-predisposing mutation disrupted the ability to both bind as well as modulate estrogen-induced 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 TN breast cancers. There are currently no targeted treatments against TN breast cancers. One of the challenges in breast cancer research is to discover new treatments that will be effective against TN breast cancers. Results from these studies will provide novel targeted therapies based on enhancing the degradation of stalled ER-alpha to reinitiate transcription offers an attractive method for the treatment of TN breast cancers. 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 TN breast cancers. The health implications of this study in Cancer health disparities are immense. We have filed several patents on this work.
Click here to view selected publications.