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

SUBMITTER: Bossard C

PROVIDER: S-EPMC3435304 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer.

Bossard Carine C Busson Muriel M Vindrieux David D Gaudin Françoise F Machelon Véronique V Brigitte Madly M Jacquard Carine C Pillon Arnaud A Balaguer Patrick P Balabanian Karl K Lazennec Gwendal G

PloS one 20120906 9

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 ...[more]

PMID: 22970307

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Project description:In attempt to discover novel aberrantly hypermethylated genes with putative tumor suppressor function in epithelial ovarian cancer (EOC), we applied expression profiling following pharmacologic inhibition of DNA methylation in EOC cell lines. Among the genes identified, one of particular interest was DOK1, or downstream of tyrosine kinase 1, previously recognized as a candidate tumor suppressor gene (TSG) for leukemia and other human malignancies. Using bisulfite sequencing, we determined that a 5'-non-coding DNA region (located at nt -1158 to -850, upstream of the DOK1 translation start codon) was extensively hypermethylated in primary serous EOC tumors compared with normal ovarian specimens; however, this hypermethylation was not associated with DOK1 suppression. On the contrary, DOK1 was found to be strongly overexpressed in serous EOC tumors as compared to normal tissue and importantly, DOK1 overexpression significantly correlated with improved progression-free survival (PFS) values of serous EOC patients. Ectopic modulation of DOK1 expression in EOC cells and consecutive functional analyses pointed toward association of DOK1 expression with increased EOC cell migration and proliferation, and better sensitivity to cisplatin treatment. Gene expression profiling and consecutive network and pathway analyses were also confirmative for DOK1 association with EOC cell migration and proliferation. These analyses were also indicative for DOK1 protective role in EOC tumorigenesis, linked to DOK1-mediated induction of some tumor suppressor factors and its suppression of pro-metastasis genes. Taken together, our findings are suggestive for a possible tumor suppressor role of DOK1 in EOC; however its implication in enhanced EOC cell migration and proliferation restrain us to conclude that DOK1 represents a true TSG in EOC. Further studies are needed to more completely elucidate the functional implications of DOK1 and other members of the DOK gene family in ovarian tumorigenesis.

Dataset Information

Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer.

Publications

Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer.

Similar Datasets

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