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Molecular and Cellular Biology, December 2008, p. 7096-7108, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00449-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Activated Androgen Receptor Downregulates E-Cadherin Gene Expression and Promotes Tumor Metastasis {triangledown}

Yan-Nian Liu,1 Ying Liu,2 Han-Jung Lee,3 Yung-Hsiang Hsu,4 and Ji-Hshiung Chen1,5*

Institute of Medical Sciences,1 Department of Medicine,2 Department of Pathology,4 Institute of Molecular and Cellular Biology, Tzu Chi University, Hualien, Taiwan,5 Department of Life Science and Institute of Biotechnology, Dong Hwa University, Hualien, Taiwan3

Received 19 March 2008/ Returned for modification 28 April 2008/ Accepted 8 September 2008

The loss of E-cadherin gene expression can cause the dysfunction of the cell-cell junction to trigger tumor metastasis. Members of the Snail family of transcription factors are repressors of the expression of the E-cadherin gene. In this study, we showed that the activated androgen receptor (AR) is a novel repressor of E-cadherin gene expression and can promote metastasis. Our results demonstrated that the activated AR could bind to the E-cadherin promoter in vitro and in vivo. The activated AR and HDAC1 had synergistic effects in downregulating E-cadherin gene expression. Treating cells with the AR ligand, dihydrotestosterone (DHT), triggered the reduction of E-cadherin expression and induced changes in cell morphology from an epithelial-like to a mesenchymal-like appearance. When nonmetastatic breast cancer cells expressing cytoplasmic AR were transplanted into mice and the mice were treated with DHT, tumors were detected at metastatic sites, whereas no tumors were detected in transplanted mice without DHT treatment. Furthermore, clinical data from breast cancer patients with invasive ductal carcinomas showed high levels of AR expression in the nuclei and low levels of E-cadherin expression. These results suggest that, similarly to Snail and Twist, the activated AR can downregulate E-cadherin expression to promote the activation of epithelial-mesenchymal transition and tumor metastasis.

* Corresponding author. Mailing address: Graduate Institute of Molecular and Cell Biology, Tzu Chi University, 701 Chung Yang Rd. Sec 3, Hualien, Taiwan. Phone: 886 3 8565301, ext. 7165. Fax: 886 3 8578386. E mail: jhc{at}mail.tcu.edu.tw

{triangledown} Published ahead of print on 15 September 2008.

Molecular and Cellular Biology, December 2008, p. 7096-7108, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00449-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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