Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor

Abstract

Summary Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for BPH.

Targeting phenotypic heterogeneity in benign prostatic hyperplasia

“…Cell type-specific changes are lost with this approach. As an example of how our group is attempting to deal with cellular heterogeneity, we recently showed that AR expression is decreased with increasing prostate volume, but only in isolated luminal epithelia (103). Stromal AR slightly increased with prostate volume, which is why AR looked unchanged in our previous whole tissue molecular signature.…”

Identification of an IL‐1‐induced gene expression pattern in AR+ PCa cells that mimics the molecular phenotype of AR− PCa cells

“…We and others have shown that IL-1β and the other major IL-1 family member, IL-1 alpha (IL-1α), can repress androgen receptor (AR) accumulation and activity. [4][5][6][7] AR is a nuclear receptor transcription factor. 8 AR and its hormone ligand, androgen, are required for prostate cell growth.…”

Transcriptional mechanisms coordinating tight junction assembly during epithelial differentiation

“…The conditional ablation of AR in prostate luminal epithelial cells results in decreased levels of CLDN3, CLDN4, and CLDN8 and widened intercellular spaces at the level of the tight junction. In addition, AR ChIP‐seq in adult male mice confirmed binding to the promoter regions of the genes encoding these proteins . Combined, these observations suggest that AR directly regulates the levels of junctional genes in the prostate epithelium.…”

“…Combined, these observations suggest that AR directly regulates the levels of junctional genes in the prostate epithelium. Since impaired tight junction integrity in the prostate epithelium is believed to be an underlying cause of age‐associated prostate diseases, such as prostate cancer and benign prostatic hypertrophy, it will be interesting to determine whether testosterone treatment in aging men can effectively increase the expression of junctional components to reestablish tight junction integrity.…”