Lxrα Regulates the Androgen Response in Prostate Epithelium

Abstract

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

Liver X Receptors Protect from Development of Prostatic Intra-Epithelial Neoplasia in Mice

“…It is therefore very likely that the prostatic phenotype of LXR-null mice is not only dependent on an epithelial cell-autonomous effect of LXR ablation. This hypothesis is supported by our previous observation that LXR were required to establish a cellular dialogue between stromal and epithelial compartments in ventral prostate [5].…”

“…These receptors heterodimerize with RXR (Retinoid X Receptor) and stimulate various target genes expression, among which, genes encoding proteins in charge of cholesterol efflux, storage and uptake. Deletion of these receptors in mouse has been previously associated with the development of benign prostatic hyperplasia (BPH) lesions in ventral prostates [4], [5]. These findings enlighten the role of LXR in prostate homeostasis.…”

“…Previous analyses of LXR null mice have shown the development of a BPH-like phenotype in the ventral lobe of the prostate [4], [5]. However in patients, BPH arises in the periurethral and transition zones distinct from the peripheral zone from which cancer emerges.…”

Differential ontogenetic exposure to obesogenic environment induces hyperproliferative status and nuclear receptors imbalance in the rat prostate at adulthood

“…Here we demonstrate that LXRα can also be regulated by HFD‐intake in rats and this deregulation could have contributed to the rise in cell proliferation and ventral prostate weight. The role of LXRα goes beyond proliferation and cell death control as it acts as a key modulator of the cross talk between the stromal and epithelial compartment, as well as deregulating androgen signaling in the prostate through a complex paracrine network . The animals used here and therefore exhibiting the same imbalance in steroid hormones showed no significant changes in weight of dorsal and lateral prostate lobes neither proliferation nor AR expression alterations (data not shown).…”

Lack of Liver X Receptors Leads to Cell Proliferation in a Model of Mouse Dorsal Prostate Epithelial Cell

“…LXRs are involved in numerous physiological regulations such as cholesterol, fatty acids and glucose homeostasis, steroidogenesis and immunity [1], [2]. Various studies have highlighted the therapeutic potential of LXR agonists in the treatment of prostate diseases such as benign prostatic hyperplasia (BPH) [3], [4] and prostate cancer [5], [6]. Indeed, LXR agonists like T0901317 slow down proliferation of various prostate cancer cell lines and decrease growth of prostate cancer cells in xenografted nude mice [7]–[9].…”