Androgen receptor control of prostate cell growth

Abstract

The androgen receptor (AR) is a member of the steroid hormone receptor superfamily. This group of ligand-dependent transcription factors is characterized by three functionally conserved domains: an N-terminal transcriptional modulation domain (NTD), a centrally located DNA binding domain (DBD) and a C-terminal hormone binding domain (BBD). Consistent with a high degree of amino acid conservation in the DBDs, this family of transcription factors shares a similar nucleic acid recognition sequence. The comparison of AR, and the closely related glucocorticoid receptor (GR), typifies the paradox of the steroid hormone receptors. Even though AR and GR can bind to and activate transcription from the same promoters in vitro, the in vivo physiological response to androgens and glucocorticoids is highly specific. Transcriptional assays were conducted using a panel of AR/GR chimeric proteins to determine the contribution of each of the functional domains to receptor specificity. Our analysis revealed that each of three domains is capable of contributing to specificity, depending on context and activity measured. A previously unidentified amino acid consensus was discovered between the two NTDs conserved among many animal species. In support of our sequence analysis, other researchers have suggested that this region contributes to activation of prostate target promoters. We have developed a transcriptional activation system utilizing the probasin prostate-specific AR promoter. This activation system has been used to study a physiologically relevant AR target promoter. The major function of androgens is to control growth and differentiation of prostate cells. The effect of AR activation was studied in CA25s cells, a cell line established in our lab by viral gene-mediated immortalization of normal rat prostate cells. Androgen treatment of CA25s cells causes a reduced proliferation rate and dramatic morphological change. This androgen dependent effect was observed only in cells that expressed AR, and no androgen dependent proliferation was observed in an AR-expressing hepatocyte-derived cell line. The reduced proliferation is not due to p21cip1 induction or an increase in apoptosis. I propose that the AR-mediated effect on CA25s cell growth is due to androgen-induced epithelial cell differentiation. This observed AR response has ramifications for prostate cancer, as the current mode of treatment relies on the paradigm that androgens act only as a proliferation signal in prostate cells.