Androgen axis in prostate cancer

✍ Scribed by Zoran Culig; Georg Bartsch

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 156 KB
• Volume: 99
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20898

✦ Synopsis

Abstract

Endocrine therapy for advanced prostate cancer is based on androgen ablation or blockade of the androgen receptor (AR). AR action in prostate cancer has been investigated in a number of cell lines, their derivatives, and transgenic animals. AR expression is heterogenous in prostate cancer in vivo; it could be detected in most primary tumors and their metastases. However, some cells lack the AR because of epigenetic changes in the gene promoter. AR expression increases after chronic androgen ablation in vitro. In several xenografts, AR upregulation is the most consistent change identified during progression towards therapy resistance. In contrast, the AR pathway may be by‐passed during chronic treatment with a nonsteroidal anti‐androgen. AR sensitivity in prostate cancer increases as a result of activation of the Ras/mitogen‐activated protein kinase pathway. One of the major difficulties in endocrine therapy for prostate cancer is acquisition of agonistic properties of AR antagonists observed in the presence of mutated AR. Enhancement of AR function by associated coactivator proteins has been extensively investigated. Cofactors SRC‐1, RAC3, p300/CBP, TIF‐2, and Tip60 are upregulated in advanced prostate cancer. Most studies on ligand‐independent activation of the AR are focused on Her‐2/neu and interleukin‐6 (IL‐6). On the basis of studies that showed overexpression and activation of the AR in advanced prostate cancer, it was suggested that novel therapies that reduce AR expression will provide a benefit to patients. There is experimental evidence showing that prostate tumor growth in vitro and in vivo is inhibited following administration of chemopreventive drugs or antisense oligonucleotides that downregulate AR mRNA and protein expression. J. Cell. Biochem. 99: 373–381, 2006. © 2006 Wiley‐Liss, Inc.