The G-Protein Coupled Estrogen Receptor (GPER/GPR30) is a Gonadotropin Receptor Dependent Positive Prognosticator in Ovarian Carcinoma Patients

Abstract

Follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) were demonstrated to impact upon survival of patients suffering from epithelial ovarian cancer (EOC). Though structure wise the G-protein coupled estrogen receptor (GPER/GPR30) is related to FSHR/LHCGR, its prognostic impact in EOC remains controversial. We recently found that FSHR negative patients represent a specific EOC subgroup that may behave differently in respect to both treatment response and prognosis. Hence, the current study aimed to analyze how GPER may interact with the FSHR/LHCGR system in EOC and whether the prognostic significance of GPER in EOC cases (n = 151) may be dependent on the FSHR/LHCGR immunophenotype of the tumor. Ovarian cancer cell lines were used to study how FSH and LH regulate GPER and whether GPER activation differentially affects in vitro cell proliferation in presence/absence of activated FSHR/LHCGR. In EOC tissue, GPER correlated with FSHR/LHCGR and was related to prolonged overall survival only in FSHR/LHCGR negative patients. Although GPER was found to be specifically induced by LH/FSH, GPER agonists (4-Hydroxy-Tamoxifen, G1) reduced EOC cell proliferation only in case of LH/FSH unstimulated pathways. To the same direction, only patients characterized as LHCGR/FSHR negative seem to gain from GPER in terms of survival. Our combined tissue and in vitro results support thus the hypothesis that GPER activation could be of therapeutic benefit in LHCGR/FSHR negative EOC patients. Further studies are needed to evaluate the impact of GPER activation on a clinical scheme.

The G-Protein Coupled Estrogen Receptor (GPER/GPR30) in ovarian granulosa cell tumors

“…Later, it was speculated that GPER may not be related to EOC patients' overall survival at all [19]. Only recently, several studies, including ours, revealed that GPER expression in EOC may be associated with a more favorable prognosis [9,20]. On the contrary, GPER was found to hold oncogenic activity in endometrial cancer [21].…”

“…GPER was detected by immunohistochemistry, as described before [9,10,18], and Ki67 immunohistochemistry was performed on a Ventana Benchmark XT autostainer, as explained elsewhere [26]. Normal ovarian tissue (GPER) and palatine tonsil tissue (Ki67) were used as positive controls.…”

“…Van Meurs et al [1] hypothesized that various response rates may be caused by different hormone receptor profiles of the respective primary tumor. To this direction, we recently highlighted the G-protein coupled estrogen receptor (GPER/GPR30) to be predictive for epithelial ovarian cancer (EOC) patient survival only in the case of missing co-expression of gonadotropin receptors [9]. We further provided in vitro evidence that gonadotropin receptor signaling may interfere with GPER action in epithelial ovarian cancer cells [9] and demonstrated GPER itself to be regulated by estrogen [10].…”

“…To this direction, we recently highlighted the G-protein coupled estrogen receptor (GPER/GPR30) to be predictive for epithelial ovarian cancer (EOC) patient survival only in the case of missing co-expression of gonadotropin receptors [9]. We further provided in vitro evidence that gonadotropin receptor signaling may interfere with GPER action in epithelial ovarian cancer cells [9] and demonstrated GPER itself to be regulated by estrogen [10]. Hence, GPER, if present in GCTs, might be considered relevant as a possible confounder when assessing the efficacy of hormone-based therapeutic approaches in GCTs.…”

Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer

“…In this manner, the relative levels of ER corepressors and coactivators can also affect tumor progression and response to hormone therapy [32, 49]. The differential functions of the various ERs play an important role in ovarian cancer as well; ERα [29, 50-53] and GPER1 [52, 54-56] are primarily thought to be protumorigenic, whereas studies report ERβ to be primarily anti-proliferative [57-60]. …”