Cited by 158Estrogen and related hormone effectsReceptor Mechanisms and SignalingEffects and risks of endocrine disrupting chemicals

Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation

Open access
Lin, Benjamin C., Suzawa, Miyuki, Blind, Raymond D., Tobias, Sandra C., Bulun, Serdar E., Scanlan, Thomas S., Ingraham, Holly A.·2009·Cancer Research

Published 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]

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-08-1622

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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 › Genetics › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review