Veena N. Rao, Ph.D.  Professor and Co-Director Cancer Biology Program, Department of Microbiology, Biochemistry & Immunology Morehouse School of Medicine M.S., Osmania University, India Ph.D., Osmania University, India E-mail: vrao@msm.edu Office Phone: 404-489-9993 Fax: 404-489-9220

Research Interests

Molecular and Functional Dissection of ELK-1 and BRCA1 tumor suppressor genes: Role in cell growth, differentiation, signal transduction, apoptosis of breast, ovarian and prostate cancers.

One of the ongoing projects in my lab is centered on 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. We have identified a member of the ETS family and named it Elk-1 (ETS-like gene). Elk-1 mediates signaling by three types of MAPKS: ERK, JNK and p38. The defective functioning of this signaling network is the root cause of widespread diseases such as cancer. Breast cancers have a decreased ability to undergo cell death. We have found the Elk-1 gene product to induce apoptosis of human breast cancer cells. We plan to study the mechanism of cell death induced by ELK-1 in cancer cells.

The second project in my lab focuses on the BRCA1 gene products.BRCA1 gene was shown to be either lost or mutated in families with breast, ovarian and prostate cancers. Among sporadic cases of breast cancer, expression of BRCA1 is reduced in high grade ductal carcinomas suggesting the involvement of this gene in the etiology of breast cancers. Majority of patients with BRCA1 mutations have triple negative breast cancers which means these tumors lack receptors for the hormones estrogen,progesterone,and for the protein HER2. We have cloned and characterized two new BRCA1 splice variants BRCA1a and BRCA1b which are undetectable in several breast and ovarian tumors. In fact we have recently obtained patent for the Splice variants of BRCA1. Using antisense BRCA1a RNA we have inhibited the endogenous BRCA1 in mouse cells and shown that mere down regulation of expression of BRCA1 is sufficient to achieve transformation. Introduction of BRCA1a into human Breast cancer cells resulted in apoptosis of these cells. Furthermore, we have found ELK-1 to be a potential downstream target of BRCA1 proteins. Both these splice variants inhibited the growth as well as Fos promoter activity. We plan to develop single cell-based assays for detecting functionally relevant changes in patients with BRCA1 mutations. Our recent results demonstrate for the first time that BRCA1a has anti-tumor activity in TN breast, hormone independent ovarian and prostate cancers. This ant-tumor activity is dependent on the presence of Rb but not p53 similar to BRCA1. These results suggest that the exon 11 sequences (AA 263-1365) which comprise approximately 60% of the BRCA1 coding sequence is dispensable for the tumor suppressor function of this protein. Majority of BRCA1-related breast cancers have a typical basal epithelial phenotype, TN, grade 3 and more prevalent in younger African American Women and Hispanic Women with breast cancer. There are currently no treatments that are effective against TN breast cancers. One of the challenges in breast cancer research is to discover new drugs or treatment strategies that will be effective against TN breast and hormone independent ovarian and prostate tumors. Results from these studies will provide new avenues in the future for molecular diagnosis and treatment of these cancers. Finally, since BRCA1a was found to be greatly reduced or absent in several breast and ovarian tumors relative to BRCA1 we can speculate that variation in the levels of expression of these isoforms can result in cancer. Such a finding would expedite the development of diagnostic tests which will aid counseling of patients with family history of breast cancer. This work will also help in defining the tumor suppressor defect that is conferred by clinical BRCA1 mutations in these cancers. Alternately, we also plan to use therapeutic agents that can activate or repress BRCA1 downstream signals involved in apoptosis for the treatment of these cancers. Results from this work will lead to improved knowledge of the functional significance of these splice variants which can be of great benefit to the patients who carry them. Our future efforts will be directed towards reducing the cancer disparities among minority populations by BRCA1 gene therapy using proteomics based sophisticated nano technologies.

Selected Publications

1. Rao, V.N., Papas, T.S. and Reddy, E.S.P. Erg, a human ets-related gene on chromosome 21: Alternative splicing, polydenylation and translation. Science, 237:635-639, 1987.

2. Rao, V.N., Huebner, K., Isobe, M., Ar-Rushdi, A., Croce, C.M., and Reddy, E.S.P. Elk, novel tissue-specific ets-related genes on chromosomes X and 14 near characteristic chromosome translocation breakpoints. Science, 244:66-70, 1989.

3. Chai, Y.L., Cui, J., Chipitsyna, G., Liao, B., Liu, S., Yezdani, M., Aysola, K., Reddy, E.S.P., and Rao, V.N. c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b mediated growth suppression in breast cancer cells. Oncogene, 20:1457-1367, 2001.

4. Ramugounder, R., Fujimura,Y., Liu, F., Jian-Ping Zou, Leo Lee, Rao, V.N., and Reddy, E.S.P. Role of Protein-Protein interactions in the anti-apoptotic function of EWS-Fli-1. Oncogene, 23, 7087-7094, 2004.

5. Chai, Y; Shao, N; Lee, L; Reddy, V.; Gabriela, O; Rao, R.; Aysola, P; Okoli, J; Partridge, E.; Reddy, E.S.P.; and Rao, V.N. "BRCA1a has antitumor activity in Triple-negative breast and ovarian and prostate cancer cells" Oncogene, 2007 Mar 26; [Epub ahead of print]