The G-protein coupled estrogen receptor (GPER/GPR30) is a gonadotropin receptor dependent positive prognosticator in ovarian carcinoma patients.
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.
Department of Obstetrics and Gynaecology, Campus Innenstadt, Ludwig-Maximilians-University of Munich, Munich, Germany.
Sabine
S
Heublein
Doris
D
Mayr
Thomas
T
Vrekoussis
Klaus
K
Friese
Simone S
SS
Hofmann
Udo
U
Jeschke
Miriam
M
Lenhard
D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D020239:Receptor Cross-Talk / Q000187:drug effects; D011960:Receptors, Estrogen / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011962:Receptors, FSH / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D011962:Receptors, FSH; D043562:Receptors, G-Protein-Coupled; D011974:Receptors, LH; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C016601:afimoxifene