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

Abstract

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 (ERβ) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ 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 ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ 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 ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients.

Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

“…Although the contradictory results might be due to cell-type specificity, our data are consistent with the observations in other cancer cells that ERa, but not ERb, plays a predominant role in the promotion of cell growth and survival (Thomas & Gustafsson 2011). While a few reports propose the proliferative and anti-apoptotic roles of ERb in cancer cells, the tumor suppressor properties of ERb have been demonstrated by the fact that overexpression of ERb results in anti-proliferative responses, whereas knockdown of ERb promotes the proliferative properties in different cancer cell types (Treeck et al 2007, 2010, Paruthiyil et al 2011, Bossard et al 2012. Moreover, a study of 24 OSCC specimens shows that the frequency of ERa expression (50%) is higher than that of ERb expression (33%) (Lukits et al 2007).…”

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

“…In support of our study showing the tumor suppressor role of ERβ, there are emerging evidences showing that ERβ has an anti-oncogenic role in the development and progression of some tumor types, including ovarian cancer, renal cell carcinoma, prostate cancer, and colon cancers. [23][24][25][26][27][28][29] Our study and these previous reports altogether indicated a protective role of ERβ in the development and progression of cancer.…”

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

“…Control (sh-Luc) and anti-AXL shRNAs were previously described (14). Luciferase-transfected MDA-MB-231 cells (MDA-MB-231-Luc) were previously described (16). RhGAS6 and the goat anti-human GAS6 antibody were purchased from R&D Systems.…”

“…Intraperitoneal treatments with 200 mg 20G7-D9/injection or saline were done twice a week for four consecutive weeks. Bone metastases were quantified by in vivo bioluminescence imaging at day 25, as described previously (16). For PDX models, approximately 60 mm 3 of B3804 and B3467 tumors were transplanted in the interscapular fat pads of Swiss nude female mice (Charles River Laboratories) and treated with 200 mg 20G7-D9 twice weekly or saline, when…”