Estrogen Receptor-Beta Regulates Epithelial Cell Differentiation in the Mouse Ventral Prostate

Abstract

The epithelium of the ventral prostate expresses high levels of ERβ (but no ERα). ERα is expressed in the stroma. Thus, in addition to the indirect effects of estrogen on the epithelium which are reported to be mediated by ERα, there is a direct estrogenic influence on prostatic epithelium mediated by ERβ. We have reported that loss of ERβ results in epithelial hypercellularity in the ventral prostate. In ERβ–/– mouse prostates, there is overexpression of the androgen receptor and of the antiapoptotic factor Bcl-2 in the prostate. Bcl-2 is an estrogen-regulated gene. It is normally expressed only in the basal cells in the prostate. This apparent expansion of the ‘stem cell-like population’ in the ERβ–/– mouse prostate has been further examined. We found a higher expression of cytokeratin 5 in ERβ–/– mouse prostates so that the ratio of cytokeratin 5 to that of 19 is much higher in ERβ–/– than in wild-type littermates. In addition, labeling of DNA with BrdU showed a 3.5-fold higher proliferation rate in ERβ–/– mouse prostate. Despite these clear differences, the piling up of epithelial cells never progressed to high-grade PIN-like lesions. Hyperplastic foci in ERβ–/– mice show accumulation of cells without signs of atypia, resembling low-grade PIN in humans. The reason for this appeared to be a high rate of cellular detachment and subsequent fall off into the lumen in ERβ–/– mice. The fall off phenomenon is possibly related to the finding that the expression of the cell adhesion molecule E-cadherin was very reduced. We conclude that in ERβ–/– mouse prostates, the epithelial cell population contains more epithelial cells in the intermediate stage of differentiation, possessing both the ability to proliferate as the basal cells and the ability to secrete as the highly differentiated luminal epithelium.