ERβ- and Prostaglandin E2-Regulated Pathways Integrate Cell Proliferation via Ras-like and Estrogen-Regulated Growth Inhibitor in Endometriosis
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In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-β (ERβ) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERβ binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERβ target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERβ at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERβ and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention.
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Aberrantly high ESR2 levels regulate several pathological processes in endometriotic tissue including proliferation, inhibition of apoptosis, inflammation and pain transmission.
“Aberrantly high ESR2 levels regulate several pathological processes in endometriotic tissue including proliferation, inhibition of apoptosis, inflammation and pain transmission”
From Endometriosis and nuclear receptors (2019) · cites this paper as Monsivais et al., 2014
The Results (p. 10) link ERβ overexpression to endometriotic stromal-cell proliferation through RERG, and the Discussion (p. 11) connects this pathway with proinflammatory signaling. The paper does not establish that ERβ inhibits apoptosis or regulates pain transmission; the Results (p. 9) say RERG is not a key regulator of apoptosis in these cells. (LLM, conf=0.88)
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- Authors
- Monsivais, D., Dyson, M. T., Yin, P., Coon, J. S., Navarro, A., Feng, G., Malpani, S. S., Ono, M., Ercan, C. M., Wei, J. J., Pavone, M. E., Su, E., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Bulun, S. E.
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2014-08-01
- Volume
- 28
- Issue
- 8
- Pages
- 1304-1315
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC4116594
- OpenAlex
- W2010229505
- Cited by
- 91
- References
- 54
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 16 · 2023: 11 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 3 · 2016: 5 · 2015: 3
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R25GM079300)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007169)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD038691)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Keywords
- endometriosis, estrogen receptor beta, prostaglandin E2, RERG, cell proliferation, endometriotic stromal cells, estradiol, protein kinase A, nuclear translocation, therapeutic target
- MeSH terms
- Adult, Cell Nucleus, Endometriosis, Estradiol, Female, Gene Expression Regulation, Humans, Dinoprostone, GTP Phosphohydrolases, Protein Transport, Estrogen Receptor beta, Cell Proliferation, HEK293 Cells
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