Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ER beta) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ER beta in BG-1 epithelial ovarian cancer cells, which express ER alpha, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ER beta reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ER beta downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ER beta had a direct effect on ER alpha, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ER beta. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ER beta expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ER beta in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients.