Research in my laboratory focuses on crosstalk between estrogen receptors and p53 signaling in breast, lung, and ovarian cancers. Inactivation of p53 by multiple mechanisms is a frequent event in these cancers. Estrogen receptors alpha (ERα) and beta (ERβ) have important roles in normal and disease physiology of these organs. We have shown that both ERα and ERβ bind p53. Binding of ERα to p53 results in functional inactivation of p53, whereas ERβ-p53 interaction elicits context-dependent effects in cancer cells.
We utilize various experimental approaches that involve cell culture models, murine models of human tumor cell xenograft and human patient–derived xenografts (PDXs) for probing molecular mechanisms underlying interaction between the estrogen receptors and p53 and its cellular consequences relevant to the onset and progression of breast, lung, and ovarian cancers. We actively pursue opportunities to translate findings from the laboratory by developing innovative retrospective and prospective clinical studies. One such prospective clinical trial to investigate the role of p53 and ERα in breast cancer resistance to tamoxifen therapy is currently underway.
Putluri, P., Maity, M., Kommangani, R., Creighton, C. J., Putluri, V., Chen, F., Nanda, S., Bhowmik, S. K., Terunuma, A., Dorsey, T., Nardone, M., Fu, X., Shaw, C., Sarkar, T.R., Schiff, R., Lydon, J. P., O’Malley, B.W., Ambs,S., Das, G. M., Michailidis, G., and Sreekumar, A. (2014). Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance. Neoplasia, 16, 330-402
Konduri, S., Medisetty, R., Liu, W., Kaipparettu, B., Srivastava, P., Brauch, H., Fritz, P., Swetzig, W., Gardner, A., Khan, S. & Das, G.M. (2010). Mechanisms of Estrogen receptor antagonism towards p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci, USA (PNAS), 107, 15081-15086. PMCID: PMC2930589.
Sayeed, A., Konduri, S., Liu, W., Bansal, S., Li, F. & Das, G.M. (2007). Estrogen receptor inhibits p53-mediated transcriptional repression: Implications for the regulation of apoptosis. Cancer Research; 67, 7746-7755, PMID: 17699779.
Liu, W., Konduri, S., Bansal, S., Nayak, B.K., Rajasekaran, S.A., Karuppayil, S.M., Rajasekaran, A.K. & Das, G.M. (2006). Estrogen receptor-α binds p53 tumor suppressor protein directly and represses its function, Accelerated Report, J Biological Chemistry; 281, 9837-9840, PMID: 16469747.
Das, G., Hinkley, C.S. & Herr, W. (1995). Basal promoter elements as a selective determinant of transcriptional activator function. Nature, 314, 657-659.