The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate

• 成果类型: Article
• 署名作者: Wu, Wan-fu; Song, Xiao-yu; Warner, Margaret; Imamov, Otabeck; Antonson, Per; Gustafsson, Jan-Ake
• 署名单位: University of Houston System; University of Houston; Karolinska Institutet
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11458
• DOI: 10.1073/pnas.2505797122
• 发表日期: 2025-07-01
• 关键词: liver x receptors; er-beta; cancer; differentiation; expression; PATHWAY; GROWTH; alpha

摘要

Estrogen receptor R (ERR) plays an important role in both the mouse and human prostate. The endogenous ligand for ERR is the dihydrotestosterone metabolite, 5R-androstane-3R, 17R-diol (3R-Adiol). Thus, treatment with 5-alpha reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERR-/- mice. By comparing RNA-Seq of the ventral prostates (VP) of ERR knockout mice (ERRcrispr-/-) and wild-type (WT) mice, we confirmed that ERR modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERRcrispr-/- mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERRcrispr-/- mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERRcrispr-/- mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERRcrispr-/- mice. We conclude that ERR is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERR agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.