Gene regulation profiles by progesterone and dexamethasone in human endometrial cancer Ishikawa H cells

Abstract

Objective.Progesterone and glucocorticoids such as dexamethasone mediate distinct biological functions, yet they bind to receptors that recognize the same consensus DNA response element. In breast cancer, progestins are associated with the incidence and progression of tumors, whereas glucocorticoids are growth-suppressive in mammary cancer cells; the differential effects of these two steroids are less well understood in the hormone-dependent disease cancer of the uterine endometrium. We set out to identify genes that are regulated by progesterone through progesterone receptors and dexamethasone through glucocorticoid receptors in a well-differentiated human endometrial cancer cell line. Methods.PR- and GR-positive Ishikawa H endometrial cancer cells were treated with vehicle, dexamethasone (100 nM) or progesterone (100 nM) for 2 h, 6 h, 12 h and 24 h, and RNA was isolated. Affymetrix microarrays were performed using the human HG-U133A chip, querying the expression of 22,000 genes. Expression of genes of particular interest was confirmed by real-time RT-PCR. Results.Expression analysis demonstrated that dexamethasone and progesterone regulate overlapping but distinct sets of genes and presumably exert many similar but also unique biological effects. Using real-time RT-PCR, we confirmed three particular genes of interest: the transcript for cysteine 1 (legumain), a gene associated with metastasis, that is strongly downregulated by progesterone, upstream c-fos relating transcription factor-2 (USF-2), an anti-proliferative factor that is induced by both progesterone and dexamethasone and N-cadherin, a cellular adhesion molecule downregulated by dexamethasone. Conclusion.These studies provide new insight into the effects of progesterone and dexamethasone in endometrial cancer cells and provide an extensive list of regulated pathways which can be assessed in the future as biomarkers and molecular targets for new therapies. Taken together, our findings indicate that progesterone and dexamethasone are primarily growth inhibitors in Ishikawa H endometrial cancer cells.