A novel estrogen receptor GPER mediates proliferation induced by 17β‐estradiol and selective GPER agonist G‐1 in estrogen receptor α (ERα)‐negative ovarian cancer cells

Abstract

G protein-coupled estrogen receptor (GPER) is recently identified as a membrane-associated estrogen receptor that mediates non-genomic effects of estrogen. Our previous immunohistochemistry study found an association between GPER and the proliferation of epithelial ovarian cancer. However, the contributions and mechanisms of GPER in the proliferation of ovarian cancers are not clear. We have examined the role of GPER in estrogen receptor α (ERα)-negative/GPER positive OVCAR5 ovarian cancer cell line. MTT assay was used to detect cell proliferation. BrdU incorporation assay was used to measure the cells in S-phase. Protein expression of marker genes of proliferation, cell cycle and apoptosis were examined by Western blot. The results showed that 17β-estradiol and selective GPER agonist G-1 stimulated the proliferation of OVCAR5 cells and increased the cells in S-phase. Both ligands upregulated the protein levels of c-fos and cyclin D1. Small interfering RNA targeting GPER or G protein inhibitor pertussin toxin (PTX) inhibited basal cell proliferation and attenuated 17β-estradiol- or G-1-induced cell proliferation. GPER mediated cell growth was also associated with the apoptosis of OVCAR5 cells. These findings suggest that GPER has an important function in the proliferation of ovarian cancer cells lacking ERα. GPER might be a promising therapeutic target in ovarian cancer.

G Protein–Coupled Estrogen Receptor Regulates Mammary Tumorigenesis and Metastasis

“…Several reports have demonstrated that multiple cancer cell lines proliferate in response to the GPER-selective agonist G-1 (36-38) and that E2-dependent proliferation can be reduced upon silencing GPER expression or inhibiting GPER activity (16, 39-41). While these data suggest GPER may promote breast tumor growth, its importance in breast cancer initiation, growth and progression has remained unexplored.…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…In addition to breast cancer cell lines and primary tumors of the breast (Carmeci et al, 1997;Filardo et al, 2000;Revankar et al, 2005;Albanito et al, 2008), GPER is also expressed in cancers and cell lines of the endometrium (Vivacqua et al, 2006a;Leblanc et al, 2007;Smith et al, 2007;He et al, 2009;Petrie et al, 2013;Dai et al, 2014), ovaries (Albanito et al, 2007(Albanito et al, , 2015Henic et al, 2009;Smith et al, 2009;Liu et al, 2014), thyroid (Vivacqua et al, 2006a), lung (Siegfried et al, 2009), prostate (Chan et al, 2010), and testes (Franco et al, 2011). In cell lines of thyroid, ovarian, endometrial, and breast cancers, stimulation of GPER with E2 (Vivacqua et al, 2006a,b;Albanito et al, 2007) or other estrogenic compounds, such as genistein (Vivacqua et al, 2006a), bisphenol A (Dong et al, 2011;Chevalier et al, 2012a), or tamoxifen (Vivacqua et al, 2006b) activates signaling mechanisms that typically promote proliferation.…”

The Role of Endocrine G Protein-Coupled Receptors in Ovarian Cancer Progression

“…Even though GPER is widely expressed in tumors, its role in ovarian cancer is controversial. An early report proposed that elevated expression levels of GPER correlate with poor prognosis (19). Activation of GPER in ER-negative cells has also been shown to promote cell migration and invasion (20).…”

“…ER-negative cells provide a clear picture of the role of GPER in ovarian cancer cell proliferation. 17β-Estradiol is a strong agonist of GPER that can enhance S-phase promotion and cell migration in ER-negative ovarian cancer cells (19, 20). Selective activation of GPER by G-1 can also activate EGFR, upregulate c-fos, cyclin D1, cyclin E, and cyclin A, and promote cell proliferation (23).…”