Abstract
BackgroundIt is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression. This study was conducted to evaluate the GPER-1 expression in ovarian cancer and its correlation with progression. Its function was tested in vitro in ovarian cancer cells.Patients and methodsGPER-1 expression was analyzed by immunohistochemistry in 35 benign ovarian tumors, 35 tumors of low-malignant potential and in 124 ovarian cancers. GPER-1 expression was correlated to the prospectively evaluated disease-free survival of ovarian cancer patients. We also tested GPER-1 expression in ovarian cancer cells and the effect of GPER-1 stimulation on cell growth.ResultsGPER-1 expression was significantly lower in ovarian cancer tissue than in benign and low-malignant ovarian tumors. GPER-1 expression was observed in 83.1% of malignant tumors and was higher in early stage cancers and tumors with high histological differentiation. GPER-1 expression was associated with favourable clinical outcome. The difference in 2-year disease-free survival by GPER-1 expression was significant, 28.6% for GPER-1 negative and 59.2% for GPER-1 positive cases (p = 0.002). GPER-1 expression was observed in SKOV-3 and OVCAR-3 ovarian cancer cell lines. G-1, a selective GPER-1 agonist, suppressed proliferation of the two cell types via inhibition of cell cycle progression in G2/M phase and stimulation of caspase-dependent apoptosis. The blockade in G2/M phase was associated with increased expression of cyclin B1 and Cdc2 and phosphorylation of histone 3.ConclusionGPER-1 emerges as a new tumor suppressor with unsuspected therapeutic potential for ovarian cancer.
Highlights
Ovarian cancer is a common neoplasm in Western countries and more than 70% of all diagnoses are in advanced stage [1,2]
G-protein-coupled estrogen receptor-1 (GPER-1) expression was significantly lower in ovarian cancer tissue than in benign and low-malignant ovarian tumors
GPER-1 expression was observed in SKOV-3 and OVCAR-3 ovarian cancer cell lines
Summary
Ovarian cancer is a common neoplasm in Western countries and more than 70% of all diagnoses are in advanced stage [1,2]. Smith and co-workers have shown in 89 ovarian cancer patients that GPER-1 expression is associated with poor survival [13]. Kolkova and co-workers have not found any correlation between GPER-1 expression and survival of 152 patients with ovarian cancer [14]. A third research group has found that GPER-1 expression predicts lower survival of 150 ovarian cancer patients only by co-expression with epidermal growth factor receptor (EGFR) [15]. In vitro studies provide controversial data regarding GPER-1 effect on cell growth [16], adding confusion to the role of GPER-1 in ovarian cancer. It is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression.
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