G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPERgene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.
The classical estrogen receptors first characterized in 1958 are water-soluble proteins located in the interior of cells that are activated by estrogenenic hormones such as estradiol and several of its metabolites such as estrone or estriol. These proteins belong to the nuclear hormone receptor class of transcription factors that regulate gene transcription. Since it takes time for genes to be transcribed into RNA and translated into protein, the effects of estrogens binding to these classical estrogen receptors is delayed. However, estrogens are also known to have effects that are too fast to be caused by regulation of gene transcription. In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) family, GPR30 also binds with high affinity to estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor (GPER). GPER is localized in the plasma membrane and can also be detected in the endoplasmic reticulum.
Although GPER signaling was originally thought to be tumor-promoting in breast cancer, subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer. Consistent with this, recent studies showed that the presence of GPER protein in human breast cancer biopsies correlates with longer survival, suggesting a tumor suppressive role. In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma, colorectal cancer, endometrial cancer, Leydig cell tumors, non-small cell lung cancer, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, and prostate cancer. Together, these reports suggest that GPER is a tumor suppressor in a wide range of cancer types, and activation of GPER may represent a new therapeutic strategy to treat cancer.
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