Evidence that epithelial and mesenchymal estrogen receptor-alpha mediates effects of estrogen on prostatic epithelium

In combination with androgens, estrogens can induce aberrant growth and malignancy of the prostate gland. Estrogen action is mediated through two receptor subtypes: estrogen receptors alpha (ERalpha) and beta (ERbeta). Wild-type (wt) and transgenic mice lacking a functional ERalpha (alphaERKO) or ERbeta (betaERKO) were treated with the synthetic estrogen diethylstilbestrol (DES). DES induced prostatic squamous metaplasia (SQM) in wt and betaERKO but not in alphaERKO mice, indicating an essential role for ERalpha, but not ERbeta, in the induction of SQM of prostatic epithelium. In order to determine the respective roles of epithelial and stromal ERalpha in this response, the following tissue recombinants were constructed with prostatic epithelia (E) and stroma (S) from wt and ERKO mice: wt-S+wt-E, alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E. A metaplastic response to DES was observed in wt-S+wt-E tissue recombinants. This response to DES involved multilayering of basal epithelial cells, expression of cytokeratin 10, and up-regulation of the progesterone receptor. Tissue recombinants containing alphaERKO-E and/or -S (alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E) failed to respond to DES. Therefore, full and uniform epithelial SQM requires ERalpha in the epithelium and stroma. These results provide a novel insight into the cell-cell interactions mediating estrogen action in the prostate via ERalpha.