Loss of epithelial oestrogen receptor α inhibits oestrogen-stimulated prostate proliferation and squamous metaplasia via in vivo tissue selective knockout models

Squamous metaplasia (SQM) is a specific phenotype in response to oestrogen in the prostate and oestrogen receptor (ER) alpha is required to mediate this response. Previous studies utilizing tissue recombination with seminal vesicle (SV) mesenchyme and prostatic ductal tips from wild type and ER alpha KO mice suggested that both epithelial and stromal ER alpha are necessary for SQM. However, tissue recombination is conducted in the renal capsule of immune-deficient mice, in which the microenvironment is different from normal prostate microenvironment in the intact mice. Furthermore, whether the requirement of stromal ER alpha in the SV for developing SQM is the same as in the prostate is unknown. Therefore, there is a clear need to evaluate the respective roles of ER alpha in prostate epithelial versus stromal compartments in the intact mouse. Here we generated a mouse model that has selectively lost ER alpha in either stromal (FSP-ER alpha KO) or epithelial prostate cells (pes-ER alpha KO) to determine the requirements of ER alpha for oestrogen-stimulated prostate proliferation and SQM. Our results indicated that FSP-ER alpha KO prostates develop full and uniform SQM, which suggests that loss of the majority (similar to 65%) of stromal ER alpha will not influence oestrogen-mediated SQM. In contrast, loss of epithelial ER alpha inhibits oestrogen-mediated prostate growth and SQM evidenced by decreasing cytokertin 10 positive squamous cell stratification and differentiation, by reduced ER alpha protein expression in SQM compared to wild type mice ER alpha, and by the presence of normal proliferative activities in the oestrogen-treated pes-ER alpha KO prostates. These in vivo results suggest that epithelial ER alpha is required for oestrogen-mediated proliferative response and could be an appropriate target for preventing aberrant oestrogen signalling in the prostate. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.