The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium

Brianna Cloke, Kaisa Huhtinen, Luca Fusi, Takeshi Kajihara, Maria Yliheikkilä, Ka Kei Ho, Gijs Teklenburg, Stuart Lavery, Marius C. Jones, Geoffrey Trew, J. Julie Kim, Eric W.F. Lam, Judith E. Cartwright, Matti Poutanen, Jan J. Brosens

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4462-4474
Number of pages13
JournalEndocrinology
Volume149
Issue number9
DOIs
StatePublished - Sep 2008

ASJC Scopus subject areas

  • Endocrinology

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    Cloke, B., Huhtinen, K., Fusi, L., Kajihara, T., Yliheikkilä, M., Ho, K. K., Teklenburg, G., Lavery, S., Jones, M. C., Trew, G., Kim, J. J., Lam, E. W. F., Cartwright, J. E., Poutanen, M., & Brosens, J. J. (2008). The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology, 149(9), 4462-4474. https://doi.org/10.1210/en.2008-0356