The goal of my research is to understand the role of PDEF and its downstream target genes in breast cancer and to use this understanding to develop novel approaches to control of breast cancer.
We previously reported that PDEF (prostate derived Ets factor) is a breast tumor associated transcription factor with a role in breast cancer progression. Additionally, PDEF expression is induced in the precancerous DCIS lesions. Moreover, evidence from other laboratories shows that PDEF is a novel mediator of increased breast cancer risk associated with the fibroblast growth factor receptor 2 locus. Together these findings demonstrate a role for PDEF in the development and progression of breast cancer.
The underlying mechanisms of PDEF action in breast cancer remain poorly understood. Our studies of the PDEF regulated genes identified CEACAM6 as a PDEF-induced molecule. Additional characterization of their function showed that down-regulation of either PDEF or CEACAM6 by siRNA causes the loss of the viability of breast tumor cell lines in vitro. Moreover, >70% of primary breast tumors showed 10-fold or higher expression of both PDEF and CEACAM6 compared to normal breast tissue. Together, these results established PDEF-CEACAM6 as a highly active novel oncogenic axis in breast cancer. These results also provide a compelling rationale to develop novel treatments for breast cancer that target the PDEF and CEACAM6 molecules.
To that purpose, we have found that immunization with Pse (prostate specific Ets, the mouse homolog of PDEF) induces specific T cell responses with anti-tumor activity. Based on these findings our research focus now is to develop PDEF-based vaccine/immunotherapy approach for prevention and treatment of breast cancer.
1. Chakravarty, P., Fuji, H., Abu-hadid, M.M. Hsu, S-C. and Sood, A.K. Tumorigenicity of IL-2 cDNA-transfected L1210 lymphoma and its in vivo variants is modulated by changes in IL-2 expression; potential therapeutic implications. Cancer Immunol. Immunother. 1992; 35: 347-354. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+1394339
2. Abu-hadid, M.M., Fuji, H., Hsu, S-C. and Sood, A.K. A one step PCR procedure for analysis of tumor specific T lymphocyte responses. J. Immunol. Methods 1996; 190: 91-105. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+2432131
3. Hsu, S-C., Glaves-Rapp, D. and Sood, A.K. IL-2 secretion by KHT sarcoma cells leads to loss of their vaccine potential. Cancer Immunol. Immunother. 1997; 44: 117-124. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+9177474
4. Ghadersohi, A. and Sood, A.K. Prostate epithelium-derived Ets transcription factor mRNA is over expressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen. Clin. Cancer Res. 2001; 7:2731-2738. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+11555586
5. Ghadersohi, A., Odunsi, K., Lele, S., Collins, Y., Greco, WR, Winston, J, Liang, P and Sood, A.K. Prostate- derived Ets factor shows better tumor-association than other cancer-associated molecules. Oncol. Rep 2004; 11: 453-458. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+14719083
6. Rodabaugh, K., Mhavech-Fauceglia, P, Lele, S and Sood, A.K. Prostate Derived Ets Factor (PDEF) is over expressed in Serous Epithelial Ovarian Tumors. Internation. J. of Gynecol Path. 2007; 26; 1:10-15. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+17197890
7. Sood, AK, Saxena, R, Groth, J, Desouki, MM, Cheewakriangkrai, C, Rodabaugh, KJ, Kasyapa, CS and Geradts, J. Expression characteristics of PDEF support a role in breast and prostate cancer progression. Hum. Pathol. 2007; 38:1621-1627. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+17521701
8. Sood, AK, Wang, J, Mhawech-Fauceglia, P, Jana, B, Liang, P, Geradts, J. Sam-pointed domain containing Ets transcription factor in luminal breast cancer pathogenesis. Cancer Epidemiol Biomar & Pev 2009; 18: 1899-1903. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+19505923
9. Sood, AK. PDEF and PDEF induced proteins as candidate antigens for T cell and antibody mediated immunotherapy of breast cancer. Immunol Res 2010; 46:206-15. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+19763888
10. Sood, AK, Kim, H and Geradts, J. PDEF in prostate cancer. The Prostate. 2012; 72:592-596. http://www.ncbi.nlm.nih.gov/pubmed/?term=21796651
11. Mukhopadhyay A, Khoury T, Stein L, Shrikant P, Sood AK. Prostate derived Ets transcription factor and Carcinoembryonic antigen related cell adhesion molecule 6 constitute a highly active oncogenic axis in breast cancer. Oncotarget. 2013; 4:610-21. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A++23592399&report=abstract