One in eight American women will be diagnosed with breast cancer in their lifetime and one six American men will be diagnosed with prostate cancer. Signaling via steroid hormones are central mediators of growth signals in most breast and prostate cancers. The focus of the Nordeen lab is to understand the molecular mechanisms that follow the binding of steroid hormones to their receptors resulting in the regulation of gene expression and altered growth of target cells. We have recently discovered an unexpected mechanism of crosstalk between progesterone and estrogen signaling. Our data suggest that the progesterone receptor can bind to an estrogen target site and that, when bound to this non-canonical DNA, recruits transcriptional co-repressors rather than co-activators. Thus DNA is serving as a functional ligand that determines how the progesterone receptor will act. Other work in the Nordeen lab involves targeting steroid receptors in cancer therapy. Work on prostate cancer models has implications for optimizing treatment of recurrent prostate cancer. In collaborative studies with David Shapiro at University of Illinois, high throughput screening has been employed to develop new types of anti-estrogens that inhibit estrogen receptor signaling in novel ways and inhibit growth of breast cancer cells and tamoxifen-resistant breast cancer cells. This screening technology is now being applied to other cancer and non-cancer targets to develop new therapeutic drugs.
1. Mao, C., Patterson, N.M., Cherian, M.T., Aninye, I.O., Zhang, C., Montoya, J.B., Cheng, J., Putt, K.S., Hergenrother, P.J., Wilson, E.M., Nardulli, A.M., Nordeen, S.K., Shapiro, D.J.. A new small molecule inhibitor of estrogen receptor alpha binding to estrogen response elements blocks estrogen-dependent growth of cancer cells. J. Biol. Chem. 283:12819-12830, 2008.
2. Cochrane, D.R., Spoelstra, N.S., Howe, E.N., Nordeen, S.K., Richer, J.K., MicroRNA 200c mitigates invasiveness of aggressive endometrial cancer and restores chemosensitivity to microtubule targeting agents. Molecular Cancer Therapeutics 8:1055-1066, 2009.
3. Zhang Y, Leung DYM, Nordeen SK, Goleva E. Estrogen inhibits glucocorticoid action via protein phosphatase 5-mediated glucocorticoid receptor dephosphorylation. Journal of Biological Chemistry 284:24542-24552, 2009.
4. Patterson N.M., Cherian M., Aninye I., Reynolds P.D., Schiff R., Hergenrother P.J., Nordeen S.K., Wilson E.M., Shapiro D.J. A small molecule works outside of the ligand binding pocket of estrogen receptor α to inhibit estrogen-regulated gene expression and block tamoxifen-resistant breast cancer cell growth. (submitted)