Submitted on January 9, 2009
Revised on March 26, 2009
Accepted on April 13, 2009
Androgen Sensitivity of Prostate Epithelium is Enhanced by Postnatal Androgen Receptor Inactivation
Ulla Simanainen1*, Keely McNamara1, Yan Ru Gao1, and David J. Handelsman1
1 ANZAC Research Institute
* To whom correspondence should be addressed. E-mail: usimanainen{at}anzac.edu.au.
Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knock-out (denoted as PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells, the latter attributable to persistent stromal AR dependent paracrine signaling. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated, but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen deprived epithelia to the aromatizable androgen testosterone (T) or its non-aromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 weeks of age and 2 weeks later treated with subdermal implantation of 1cm silastic tubing filled with crystalline T or DHT for a further week. Following castration, and removal of androgen action from both stromal and epithelial cells, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO but full regrowth was only observed in controls treated with aromatizable T. In PEARKO prostate androgen (T and DHT) treatment induced significant epithelial cell "shedding" into the lumen, with T treatment resulting in severe acinar disorganization, cyst formation and aberrant epithelial structures, described as a "gland within a gland". These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signalling mediated by stromal AR activity leading to indirectly androgen induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens.
