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

Abstract

Abstract 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.

Keywords

• G protein‐coupled estrogen receptor‐1
• high‐grade serous carcinoma of the ovary
• ovarian clear cell carcinoma
• progression‐free survival
• proliferation