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

Abstract

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.

ACKNOWLEDGMENTS

We thank Y. L. Juang and Z. I. Yeh for comments on the manuscript and M. H. Wang and Y. Y. Chiang for assistance in the transplantation study. We also thank H. Y. Kao for providing HDAC1 and HDAC3 cDNA expression vectors and members of the Chen laboratory for technical assistance, discussion, and suggestions.

This work was supported by grants from the National Science Council, Taiwan (NSC 91-23320-B-320-012).