Molecular Basis of Steroid Action in the Prostate.

Abstract

Androgens acting via androgen receptor (AR) play essential roles in the prostate development, growth and pathogenesis of benign prostate hyperplasia (BPH) and prostate cancer. Over the last three decades, intensive studies have been carried out to elucidate the molecular basis of androgen action in the prostate. It has been realized that there are two natural potent androgens in the mammal including humans. Although testosterone is the major androgen secreted from the testes, dihydrotestosterone (DHT) is the main androgen in the prostate to mediate the androgen action via the AR. Only one AR has been identified up to date, a member of the steroid/nuclear receptor superfamily, which is a ligand-dependent nuclear transcription factor. When androgens bind to the AR, this results in a conformational change within the AR, leading to the recruitment of co-regulators and transcription factors which mediate androgen-target gene expression. Androgen actions in the prostate can also be modulated by other hormones such as estrogens via estrogen receptors (ER). There are two known isoforms of the ER, ERα and ERβ, which are both co-expressed with AR in the prostate and prostate tumor cells, which provides an anatomical basis for a direct interplay between AR and ER. Although it is well known that androgens are important for prostate development and for the pathogenesis of BPH and prostate cancer, the precise mechanisms as to how androgens control these processes are not yet fully understood. Furthermore, evidence for the direct modulation of androgenAR actions by other hormones within the prostate or prostate tumor cells is emerging, and the clinical implications of these hormones is being explored. In this article, we will assess the importance of androgens, and especially DHT, in prostate physiology and in the pathogenesis of BPH and prostate cancer. We will also review the molecular nature of the interactions between AR and ER and their respective ligands in prostate cells, as well their potential clinical implications.