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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Proliferation
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Estrogen Receptor beta / genetics
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Estrogen Receptor beta / physiology*
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Female
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Genes, Tumor Suppressor*
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Humans
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Neoplasms, Glandular and Epithelial / genetics
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Neoplasms, Glandular and Epithelial / pathology
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Neoplasms, Glandular and Epithelial / physiopathology*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Ovarian Neoplasms / physiopathology*
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Phosphorylation
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Retinoblastoma Protein / metabolism
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Transcription, Genetic
Substances
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Estrogen Receptor beta
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Retinoblastoma Protein
Grants and funding
This work was supported by grants from ARC (Association pour la Recherche contre le Cancer, Grant No. 3582) (
http://www.arc-cancer.net), The Ligue Nationale Contre le Cancer (
http://www.ligue-cancer.net). Muriel Busson was supported by FRM (Fondation pour la Recherche Médicale) (
http://www.frm.org). DV was a recipient of the Ligue Nationale contre le Cancer. CB was supported by a HFSP fellowship (
http://www.hfsp.org/). The K. B. lab is supported by the Agence Nationale de la Recherche (ANR, grant number 2010 JCJC 1104 01) (
http://www.agence-nationale-recherche.fr/), the Université Paris-Sud, the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Ligue Nationale Contre le Cancer (Comité Val d'Oise), and is a member of the Laboratory of Excellence LERMIT (Laboratory of Excellence in Research on Medication and Innovative Therapeutics) supported by a grant from ANR (Investissements d´Avenir). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.