The androgen receptor in hormone-refractory prostate cancer

Abstract

Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling. However, the effect is short-lived, as nearly all tumours progress to a hormone-refractory (HR) state, a lethal stage of the disease. Intuitively, the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR tumours. However, there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours. AR signalling can be activated in HR tumours through several mechanisms. First, activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens. Also, mutations in the AR can change AR ligand specificity, thereby allowing it to be activated by non-steroids or anti-androgens. Finally, overexpression of the wild-type AR sensitizes itself to low concentrations of androgens. Therefore, drugs targeting AR signalling could still be effective in treating HRPC.

Figure 1

Progression from hormone-sensitive to hormonerefractory prostate cancer (HRPC). Advanced prostate cancer is initially hormone sensitive and can be effectively treated by hormone therapy, with either castration and/or anti-androgens. However, almost all patients progress to HRPC, a lethal state of the disease.

Figure 2

The androgen recepter (AR) is a ligand-activated transcription factor. (A): Schematic map of the major functional units in the AR, a 919-amino-acid protein. The AR contains the activation function 1 (AF1) at the N-terminus, the DNA-binding domain (DBD) in the middle, the ligand-binding domain (LBD) and the activation function 2 (AF2) at the C-terminus, and the nuclear localization signal (NLS) in the hinge region between the DBD and LBD. (B): AR activation. Androgens such as testosterone (T) and dihydrotestosterone (DHT) bind to the AR and result in dissociation from the heat shock protein chaperone complex (AR-HSPs). Androgen-bound AR (A-AR) translocates into the nucleus, binds to AR response elements (AREs) and activates the transcription of its target genes.