Evidence That Epithelial and Mesenchymal Estrogen Receptor-α Mediates Effects of Estrogen on Prostatic Epithelium

Abstract

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.

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

“…1 Weihua et al 2 demonstrated that 5a-androstane-3b,17b-diol (3bAdiol) is an endogenous ER b ligand. Cytochrome P450 (CYP) 7B1 and 3b-hydroxysteroid dehydrogenase (3b-HSD) are two enzymes that may determine the 3bAdiol levels available at the ER b and hence affect the regulation of prostate proliferation.…”

Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice

“…Serum T was determined using a T double antibody radioimmunoassay kit (Diagnostic System Laboratories, Inc., Webster, TX, USA). The lowest detectable T concentration is 2.0 pg ml 21 . Animals used in the hormone studies were approximately 3 months of age.…”

“…A growing body of evidence has suggested that Prostate branching morphogenesis in FSP-ERaKO mice M Chen et al 552 estrogen signaling exerts a direct impact on prostate pathogenesis and cancer. 18,21,43,44 Previous studies from conventional ER KO mice revealed that ERa, not ERb, is the critical receptor to mediate the estrogens response in those processes. 7,8,19,21 To investigate the in vivo roles of ERb in mouse prostate development, the neo-ERbKO mouse model was applied.…”

“…18,21,43,44 Previous studies from conventional ER KO mice revealed that ERa, not ERb, is the critical receptor to mediate the estrogens response in those processes. 7,8,19,21 To investigate the in vivo roles of ERb in mouse prostate development, the neo-ERbKO mouse model was applied. The neo-ERbKO male mice from Chapel Hill revealed a hyperplastic prostate, 13 while the same transgenic mice housed at Karolinska Institute presented with prostatic intraepithelial neoplasia.…”

“…In the rodent prostate, ERa is detectable in both epithelial and stromal cells. 16,[19][20][21] To date, several studies focused on ERa roles in high-dose estrogen-mediated squamous metaplasia (SQM) and carcinogenesis. 20,22,23 However, no in vivo model has effectively evaluated the roles of epithelial vs. stromal fibroblast ERa during normal prostate development.…”