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Research Articles: Therapeutics, Targets, and Development

The relevance of estrogen receptor-ß expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment

¹ Departments of Urology and ² Pathology and ³ Institute for Human Genetics, Georg-August-University, Göttingen, Germany

Requests for reprints: Paul Thelen, Department of Urology, Georg-August-University, 37099 Göttingen, Germany. Phone: 49-551-398651; Fax: 011-49-551-396165. E-mail: pthelen{at}gwdg.de

Abstract

In the prostate, estrogen receptor ß (ERß), the preferred receptor for phytoestrogens, has features of a tumor suppressor. To investigate the mechanisms underlying the beneficial effects on prostate cancer of histone deacetylase inhibitor valproic acid (VPA) and phytoestrogen tectorigenin, we analyzed the expression of ERß after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERß expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 µmol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERß. Control transfections were done with luciferase (LUC) siRNA. Expression of ERß was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERß mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERß was knocked down by siRNA, the expression of prostate-derived Ets factor, prostate-specific antigen, prostate cancer–specific indicator gene DD3^PCA3, insulin-like growth factor-1 receptor, the catalytic subunit of the telomerase, and ER was up-regulated and the tectorigenin effects were abrogated. ERß levels were diminished in prostate cancer and loss of ERß was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERß increases the expression of genes highly relevant to tumor cell proliferation. In addition, we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERß resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERß in tumor cells, could become useful in the intervention of prostate cancer. [Mol Cancer Ther 2007;6(10):2626–33]

Grant support: Horst-Müggenburg-Stiftung (P. Burfeind and P. Thelen) and Vereinigung Norddeutscher Urologen e. V. (M. Stettner).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/21/07; revised 7/24/07; accepted 8/30/07.

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