The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium
Open accessAbstract
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.
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“[60,61], who showed that AR and PR regulated distinct genomic pathways during decidualisation, consistent with a role for androgens (either local or peripheral) in regulation of fertility.”
BackgroundRegulation of androgen action during establishment of pregnancy
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- Authors
- 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.
- Affiliations
- Hammersmith Hospital (GB)
- University of Turku (FI)
- Department of Physiology (K.H., M.Y., M.P.), Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Cancer Research UK (GB)
- University Medical Center Utrecht (NL)
- Northwestern University (US)
- St George's, University of London (GB)
- Corresponding author
- Brosens, Jan J.
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-05-29
- Volume
- 149
- Issue
- 9
- Pages
- 4462-4474
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC5393297
- OpenAlex
- W2055035644
- Cited by
- 159
- References
- 63
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 6 · 2017: 15 · 2016: 7 · 2015: 6 · 2014: 12 · 2013: 11 · 2012: 12
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Funders
- Wellcome Trust
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD044715)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- androgen receptor, progesterone receptor, decidualization, endometrial stromal cells, gene regulatory networks, cytoskeletal organization, stress fiber formation, cell motility, cell cycle regulation, Wnt/β-catenin signaling, TGF-β/Smad signaling, STAT signaling, embryo implantation, maternal-fetal interaction
- MeSH terms
- Cells, Cultured, Decidua, Endometrium, Female, Gene Expression Regulation, Humans, Protein Processing, Post-Translational, Receptors, Androgen, Receptors, Progesterone, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, SUMO-1 Protein, Gene Regulatory Networks
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