Differential expression of estrogen receptor subtypes in ovarian high-grade serous carcinoma and clear cell carcinoma

Purpose To investigate the role of estrogen receptors (ERs) in high-grade serous carcinoma (HGSC) and clear cell carcinoma (CCC) of the ovary and evaluate ERs as prognostic biomarkers for ovarian cancer. Methods This study included 79 patients with HGSC (n = 38) or CCC (n = 41) treated at our institution between 2005 and 2014. Immunohistochemistry examined protein expression of ERα, ERβ, and G protein-coupled estrogen receptor-1 (GPER-1); relationships between ERα, ERβ, and GPER-1 with patient survival were evaluated. Additionally, cell proliferation assay and phosphokinase proteome profiling were performed. Results In HGSC patients, expression of ERα, cytoplasmic GPER-1, or nuclear GPER-1 was associated with poor progression-free survival (PFS) (P = .041, P = .010, or P = .013, respectively). Cytoplasmic GPER-1 was an independent prognostic factor for PFS in HGSC patients (HR = 2.83, 95% CI = 1.03-9.16, P = .007). ER expressions were not associated with prognosis in CCC patients. GPER-1 knockdown by siRNA reduced the cells number to 60% of siRNA-control-treated cells (P < .05), and GPER-1 antagonist, G-15 inhibited two HGSC cell lines proliferation (KF and UWB1.289) in a dose-dependent manner. Phosphoprotein array revealed that GPER-1 silencing decreased relative phosphorylation of glycogen synthase kinase-3. Conclusions High GPER-1 expression is an independent prognostic factor for PFS in HGSC patients, and GPER-1 may play a role in HGSC cell proliferation.