The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Stimulating the GPR30 Estrogen Receptor with a Novel Tamoxifen Analogue Activates SF-1 and Promotes Endometrial Cell Proliferation
Open accessPublished version of a preprint
Abstract
Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERα and ERβ nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERα or ERβ. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers. [Cancer Res 2009;69(13):5415–23]
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1 retracted
Vivacqua, A., Bonofiglio, D., Albanito, L., Madeo, A., Rago, V., Carpino, A., Musti, A. M., Picard, D., Andò, S., & Maggiolini, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.026344 · Cited by 280
RetractedA transmembrane intracellular estrogen receptor mediates rapid cell signaling
Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B., & Prossnitz, E. R. (2005) · Science · doi:10.1126/science.1106943 · Cited by 2,302
A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer
The Breast International Group (BIG) 1-98 Collaborative Group (2005) · New England Journal of Medicine · doi:10.1056/nejmoa052258 · Cited by 1,584
Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase
Simoncini, T., Hafezi‐Moghadam, A., Brazil, D. P., Ley, K. F., Chin, W. W., & Liao, J. K. (2000) · Nature · doi:10.1038/35035131 · Cited by 1,436
Identity of an Estrogen Membrane Receptor Coupled to a G Protein in Human Breast Cancer Cells
Thomas, P., Pang, Y., Filardo, E. J., & Dong, J. (2004) · Endocrinology · doi:10.1210/en.2004-1064 · Cited by 1,410
Filardo, E. J., Quinn, J. A., Bland, K. I., & Frackelton, A. R. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.10.0532 · Cited by 1,387
Filardo, E. J., Quinn, J. A., Frackelton, A. R., & Bland, K. I. (2002) · Molecular Endocrinology · doi:10.1210/mend.16.1.0758 · Cited by 907
Virtual and biomolecular screening converge on a selective agonist for GPR30
Bologa, C., Revankar, C. M., Young, S. M., Edwards, B. S., Arterburn, J. B., Kiselyov, A. S., Parker, M. A., Tkachenko, S. E., Savchuk, N., Sklar, L. A., et al. (2006) · Nature Chemical Biology · doi:10.1038/nchembio775 · Cited by 819
Burney, R. O., Talbi, S., Hamilton, A. E., Vo, K. C., Nyegaard, M., Nezhat, C. R., Lessey, B. A., & Giudice, L. C. (2007) · Endocrinology · doi:10.1210/en.2006-1692 · Cited by 735
Integration of the extranuclear and nuclear actions of estrogen
Levin, E. R. (2005) · Molecular Endocrinology · doi:10.1210/me.2004-0390 · Cited by 708
Cited by
Sorted by citations
The G-protein-coupled estrogen receptor GPER in health and disease
Prossnitz, E. R., & Barton, M. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.122 · Cited by 925
“In turn, these signaling pathways also activate other transcription factors, such as steroidogenic factor 1”
BackgroundEstrogen biology: New insights into GPER function and clinical opportunities
Prossnitz, E. R., & Barton, M. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.02.002 · Cited by 404
The unfolding stories of GPR30, a new membrane-bound estrogen receptor
Maggiolini, M., & Picard, D. (2010) · Journal of Endocrinology · doi:10.1677/joe-09-0242 · Cited by 360
Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors
Meyer, M. R., Clegg, D. J., Prossnitz, E. R., & Barton, M. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02237.x · Cited by 338
Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease
Schimmer, B. P., & White, P. C. (2010) · Molecular Endocrinology · doi:10.1210/me.2009-0519 · Cited by 268
Metadata
- Authors
- Lin, B. C., Suzawa, M., Blind, R. D., Tobias, S. C., Bulun, S. E., Scanlan, T. S., & Ingraham, H. A.
- Affiliations
- 1Pharmaceutical Chemistry and Departments of
- University of California, San Francisco (US)
- Northwestern University (US)
- Oregon Health & Science University (US)
- Venue
- Cancer Research
- Published
- 2009-07-01
- Volume
- 69
- Issue
- 13
- Pages
- 5415-5423
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2756996
- OpenAlex
- W2103019385
- Cited by
- 157
- References
- 51
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 3 · 2023: 9 · 2022: 8 · 2021: 5 · 2020: 8 · 2019: 11 · 2018: 5 · 2017: 2 · 2016: 13 · 2015: 18 · 2014: 15 · 2013: 11 · 2012: 11
- FWCI
- 7.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of California, San Francisco
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK063592, R01DK072246)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- GPR30, G protein-coupled estrogen receptor, tamoxifen analogues, SF-1, steroidogenic factor 1, endometrial proliferation, endometriosis, endometrial cancer, PI3K signaling, MAPK signaling, phosphatidylinositol 3,4,5-trisphosphate, aromatase, genistein, estrogen signaling, choriocarcinoma
- MeSH terms
- Animals, Breast Neoplasms, Cell Division, Choriocarcinoma, Endometriosis, Estrogens, Female, Humans, Luciferases, Pregnancy, Receptors, Estrogen, Uterine Neoplasms, Endometrial Neoplasms, Genes, Reporter, Mice, Knockout, Receptors, G-Protein-Coupled, Cell Line, Tumor, Mice, Steroidogenic Factor 1
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