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Steroid hormone receptors, including estrogen and progesterone receptors, regulate both normal and pathological growth of uterine, breast and ovarian cancers. Steroid hormone receptors function as ligand-dependent transcription factors which control target gene expression. Upon steroid binding, receptors localize to the nucleus, bind steroid response elements in gene promoters, and regulate transcription. Recently, steroid receptors have been shown to localize to the plasma membrane, associate with membrane proteins, and function as signal transduction molecules—this activity of steroid receptors is termed extranuclear, nongenomic or nonclassical action.
Endometrial cancer is the most common invasive gynecological cancer and the fourth most common cancer in women in the U.S.. Projections indicate that there will be 41,200 new cases and an estimated 7,350 deaths in 2008. The predominant, hormone dependent form of endometrial cancer, designated Type 1, is associated with a constellation of clinical findings including obesity, hypertension, and diabetes. It is estimated that up to 80% of endometrial cancers are hormone dependent, are linked to unopposed actions of excess estrogens, and it is predicted that increasing obesity rates will lead to increases in Type 1 endometrial cancer.
The goal of my research is to determine the impact and mechanisms of extranuclear estrogen / estrogen receptor signaling on endometrial cancer cell growth. We are testing three main hypotheses: 1.) nonclassical estrogen / estrogen receptor signaling promotes cyclin D1 nuclear localization, thereby stimulating the cell cycle, 2.) the estrogen receptor forms membrane complexes with known signaling molecules to activate signal transduction modules, and 3.) extranuclear estrogen receptor action regulates the growth inhibitory functions of the PTEN tumor suppressor. We utilize molecular and biochemical techniques, as well as innovative new technologies to address these questions.
Our preliminary results suggest that the extranuclear actions of the estrogen receptor are a central component of estrogen mediated endometrial cancer cell growth and provide new targets of estrogen action for therapeutic intervention.
1. Jackson, TA, Richer, JK, Bain, DL, Takimoto, DS, Tung, L and Horwitz, K. The Partial Agonist Activity of Antagonist-Occupied Steroid Receptors Is Controlled by a Novel Hinge Domain-Binding Coactivator L7/SPA and the Corepressors N-CoR or SMRT. Mol. Endcocrinol. 1997, 11,693-705.
2. Haughian, JM, Jackson, TA, Koterwas, DM and Bradford AP. Endometrial Cancer Cell Survival and Apoptosis is Regulated by Protein Kinase C Alpha and Delta. Endocrine-Related Cancer 2006, 13, 1-18.
3. Jackson TA, Koterwas DM, Bradford AP. Differential regulation of cell growth and gene expression by FGF-2 and FGF-4 in pituitary lactotroph GH4 cells. Mol Cell Endocrinol. 2006, 247(1-2):183-91.