Altered androgen metabolism and signalling during tissue remodelling of the prostatic stroma: implications for prostate cancer and benign prostatic hyperplasia
Natalie Sampson1, Eugen Plas2 & Peter Berger1
The human prostate is highly susceptible to benign and malignant proliferative changes and is associated with the development of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common diseases affecting elderly males. The diseased-associated stroma undergoes significant remodelling, including fibroblast-to-myofibroblast/smooth muscle cell transdifferentiation. Subsequent increased secretion of cytokines and growth factors generates a growth favouring microenvironment that promotes stromal hyperplasia and neoplastic transformation of pre-malignant epithelial cells. Microarray and quantitative PCR of in vitro transdifferentiated primary prostatic stromal cells changes in enzymes that regulate local androgen metabolism and signal transduction. We demonstrate that prostate-associated gene 4 (PAGE4), a cancer/testis antigen, is a novel corepressor of the androgen receptor (AR). Overexpression of PAGE4 inhibits mRNA and protein expression of endogenous androgen-regulated genes and also inhibits AR-mediated transactivation of hormone-responsive reporter constructs. Yeast two hybrids screening indicate that PAGE4 may repress AR transactivation by sequestering AR coactivator proteins, such as nuclear receptor interacting protein (NRIP). PAGE4 is induced during fibroblast-to-myofibroblast transdifferentiation and is up-regulated in BPH stroma indicating that repression of the androgen signal by PAGE4 may facilitate stromal tissue remodelling and thus disease development/progression. PCa progression to hormone refractory status is associated with aberrations in AR signalling that permit continued AR transactivation despite androgen withdrawal treatment. PAGE4 expression is downregulated during PCa progression and its absence may provide a mechanism by which AR activity is maintained in advanced disease. Collectively, these data indicate that therapies designed to target PAGE4 may be of clinical benefit in BPH and PCa.