Abstract

New directions in endocrine therapy: renewed interest in the androgen receptor

Author(s): Zoran Culig and Alfred Hobisch

Androgen ablation is the mainstay treatment for non-organ-confined prostate cancer. This treatment is only palliative and patients may present with disease progression because of changes in androgen signaling and other pathways. The androgen receptor (AR) could be activated in a ligand-dependent and -independent manner. Small concentrations of dihydrotestosterone present in tissues from patients with advanced prostate cancer are sufficient to activate the AR. Ligand-independent activation of the AR has been described for various cellular regulators. However, its significance for tumor progression in vivo has yet to be completely clarified. During androgen ablation, there is an increase in expression of several coactivators that contribute to AR hypersensitivity. In the majority of prostate cancers, the fusion of the TMPRSS2 gene and a member of the transcription factor ETS family were detected. The main problem associated with the development of therapy resistance in prostate cancer is the inability to develop therapies that block proliferation and anti-apoptotic function in contrast to the prodifferentiation function of the AR.