Abstract
BackgroundEstrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormone-dependent cancer like in tumors of the breast, ovary or prostate. In this study, we intended to further elucidate its role in endometrial cancer.MethodsFor this purpose, we knocked down ERβ expression in two endometrial cancer cell lines, the ERα-negative/ERβ-positive line HEC-1A and the ERα/β-positive cell line RL95/2, by means of siRNA transfection. Cell proliferation after transfection was assessed using the fluorescent CTB Assay (Promega). In order to elucidate possible molecular mechanisms which might underlie the effect on proliferation, we performed transcriptome analyses by means of human Affymetrix Human Gene Chip 2.0. Additionally, we treated the employed cell lines with different ERβ modulators to examine their effect on proliferation.ResultssiRNA-mediated knockdown of ERβ significantly increased proliferation of both endometrial cancer cell lines. In HEC-1A cells, proliferation was significantly increased 4, 5 and 6 days after transfection, with a maximum of about 1.7-fold (p < 0.05) on day 6. Endometrial RL95/2 cells with an ERβ knockdown exhibited a clearly enhanced proliferation on day 3 and days 4 to 8, when even 2.4-fold higher numbers of viable cells were detected (p < 0.01). Transcriptome analysis revealed that this was accompanied by increased expression of several genes being known to be upregulated in cancer, including proliferation-associated genes and oncogenes, and by repression of genes associated with differentiation, apoptosis or growth inhibition. Corroborating the observed knockdown effects, treatment with the ERβ antagonists PHTTP and (R, R) THC was also able to induce proliferation of both cell lines.ConclusionsOur data clearly support the putative role of ERβ as tumor suppressor in endometrium as previously suggested in studies on other tissues and encourage further studies to find out to what extent this molecule might be a potential therapy target in this cancer entity.
Highlights
Estrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormonedependent cancer like in tumors of the breast, ovary or prostate
In HEC-1A cells, ERβ protein levels were found to be reduced to 28.7% after ESR2 siRNA transfection, whereas in RL95/2 cells, protein levels of this gene were reduced to 39.5%
In HEC-1A cells, a statistically significant increase of proliferation was detected on days 4, 5 and 6 after transfection, with a maximum 1.7-fold increase measured on day 6 (p < 0.05)
Summary
Estrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormonedependent cancer like in tumors of the breast, ovary or prostate. Endometrial cancer is the most common malignancy of the genital tract among women in western countries. Type 1 endometrial cancer, known as endometrioid endometrial carcinoma, is the most frequent subgroup (80%), and shows estrogen and progesterone receptor expression. It emerges from hyperplastic endometrial tissue and often is characterized by PTEN loss in 37–61% of all cases. Type 2 endometrial cancer, including serous (10–15% of all cases) and clear cell carcinoma (about 5%) [3] is characterized by frequent loss of E-Cadherin or by HER2 overexpression [4]. Alterations of ER and PR expression, as well as the ERα/β ratio, have been suggested to be involved in the development of endometrial cancer and loss of these receptors during carcinogenesis has been reported to be associated with an aggressive clinical course and a poorer survival of endometrial cancer patients [5, 6]
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