Estrogenic effects on prostatic differentiation and carcinogenesis

Estrogens, alone or in combination with androgens, can induce aberrant growth and/or malignancy of the prostate gland. Squamous metaplasia is an abnormal form of prostatic epithelial differentiation elicited by exogenous estrogen alone. Estrogens elicit their effects via estrogen receptors (ER) in the prostate. Experiments using ER alpha and ER beta null mice demonstrated that ER alpha, but not ER beta is essential in the induction of prostatic squamous metaplasia. To determine the respective roles of epithelial versus stromal ERa in this response, the following tissue recombinants were constructed with prostatic epithelium (PRE) and stroma (S) from wild-type (wt) and ER alpha knockout (alpha ERKO) mice: wt-S + wt-PRE, alpha ERKO-S - alpha ERKO-PRE, wt-S + alpha ERKO-PRE and alpha ERKO-S + wt-PRE. A metaplastic response to diethylstilbestrol (DES) was only observed in wt-S + wt-PRE tissue recombinants. Tissue recombinants containing alpha ERKO-PRE and/or alpha ERKO-S (alpha ERKO-S + alpha ERKO-PRE, wt-S + alpha ERKO-PRE and alpha ERKO-S + wt-PRE) failed to respond to DES. Therefore, full and uniform epithelial squamous metaplasia requires ERa in both the epithelium and stroma. Estradiol (E2) in combination with testosterone (T) was shown to be effective in inducing prostatic carcinogenesis in a tissue recombinant model composed of rat urogenital sinus mesenchyme plus mouse prostatic epithelium. A particularly efficient model of prostatic carcinogenesis in mice involves T + E2 treatment of mice bearing grafts of wild-type rat urogenital mesenchyme (rUGM) plus retinoblastoma gone (Rb) knockout (Rb-KO) prostatic epithelium (rUGM + Rb-KO-PRE). Such rUGM + Rb-KO-PRE tissue recombinants developed hyperplasia, atypical hyperplasia and invasive prostatic carcinoma with high efficiency. During carcinogenesis in rUGM + Rb-KO-PRE tissue recombinants, epithelial E-cadherin almost totally disappeared and epithelial PCNA labeling was elevated. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. The results of this study demonstrate that the absence of the Rb tumor suppressor gene predisposes prostatic epithelial cells to hormonal carcinogenesis.