Estrogenic effects on prostatic differentiation and carcinogenesis

Estrogens, alone or in combination with androgens, can induce aberrant grow th and/or malignancy of the prostate gland. Squamous metaplasia is an abnor mal form of prostatic epithelial differentiation elicited by exogenous estr ogen alone. Estrogens elicit their effects via estrogen receptors (ER) in t he 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 s quamous metaplasia. To determine the respective roles of epithelial versus stromal ERa in this response, the following tissue recombinants were constr ucted with prostatic epithelium (PRE) and stroma (S) from wild-type (wt) an d 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 re sponse to diethylstilbestrol (DES) was only observed in wt-S + wt-PRE tissu e 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 epitheli al squamous metaplasia requires ERa in both the epithelium and stroma. Estr adiol (E2) in combination with testosterone (T) was shown to be effective i n inducing prostatic carcinogenesis in a tissue recombinant model composed of rat urogenital sinus mesenchyme plus mouse prostatic epithelium. A parti cularly efficient model of prostatic carcinogenesis in mice involves T + E2 treatment of mice bearing grafts of wild-type rat urogenital mesenchyme (r UGM) plus retinoblastoma gone (Rb) knockout (Rb-KO) prostatic epithelium (r UGM + Rb-KO-PRE). Such rUGM + Rb-KO-PRE tissue recombinants developed hyper plasia, atypical hyperplasia and invasive prostatic carcinoma with high eff iciency. During carcinogenesis in rUGM + Rb-KO-PRE tissue recombinants, epi thelial E-cadherin almost totally disappeared and epithelial PCNA labeling was elevated. These epithelial changes were associated with almost total lo ss of smooth muscle cells in the stroma. The results of this study demonstr ate that the absence of the Rb tumor suppressor gene predisposes prostatic epithelial cells to hormonal carcinogenesis.