Local endocrine, paracrine and redox signaling networks impact estrogen and androgen crosstalk in the prostate cancer microenvironment.

Androgen receptor (AR) signaling is essential for the initial development and progression of prostate cancer (PCa) as well as the growth and survival of castration-resistant tumors. However, AR action may be opposed by estrogen receptor beta (ERß) that responds to androgen metabolites produced in the prostate. The balance between the activity of these two receptors is not only influenced by the steroidogenic capacity of the prostatic microenvironment but also by its redox status and local paracrine signals such as transforming growth factor-beta (TGF-ß). In this review, we highlight the studies that revealed select roles for AR and ERß in distinct compartments of the prostate cancer microenvironment. We also discuss new work that identified stromal-epithelial crosstalk through TGF-ß1 signaling that drives the production of reactive oxygen species in stromal cells thereby selectively limiting the anti-tumor activity of ERß in cancer cells. Therefore, any new therapeutic approaches that seek to limit AR but enhance ERß activity in PCa, must take into account potential adaptive changes in the tumor microenvironment that utilize paracrine signals and altered redox balance to divert local androgen metabolites towards AR at the expense of ERß.