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The Androgen and Progesterone Receptors Regulate Distinct Gene Networks and Cellular Functions in Decidualizing Endometrium

Institute of Reproductive and Developmental Biology (B.C., L.F., T.K., S.L., M.C.J., G.T., J.J.B.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom and Department of Physiology (K.H., M.Y., M.P.), Institute of Biomedicine, University of Turku, 20520 Turku, Finland; Department of Obstetrics and Gynecology (T.K.), Saitama Medical School, Moroyama, Saitama, Japan; Cancer Research UK Labs (K.-K.H., E.W.-F.L.), Department of Oncology, Imperial College London, London W12 ONN, United Kingdom; Department of Reproductive Medicine and Gynecology (G.T.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; Department of Obstetrics and Gynecology (J.J.K.), Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 60611; and Division of Basic Medical Sciences (J.E.C.), St. George’s, University of London, London SW17 0BZ, United Kingdom

Address all correspondence and requests for reprints to: Jan Brosens, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom. E-mail: j.brosens{at}imperial.ac.uk.

Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/β-catenin, TGFβ/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.