The expression of estrogen receptors is associated with steroid 5-alpha reductase 2 in prostatic tissue
Christina Sharkey, MLA, Xingbo Long, MD, Aria F. Olumi, MD, Zongwei Wang, PhD.
Beth Israel Deaconess Medical Center, Boston, MA, USA.
BACKGROUND: Benign prostatic hyperplasia (BPH) is a highly prevalent health problem among elderly men. Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. However, patients respond very differently to 5α-reductase inhibitors (5ARIs). Our previous study demonstrated an “androgenic to estrogenic switch” when SRD5A2 is absent in the prostate gland. Here we wished to identify if estrogen receptors (ER) expression is associated with SRD5A2 in the prostate.
METHODS: 18 prostatic specimens collected from patients who underwent transurethral resection of the prostate were used to determine the transcript and protein expressions of ERα and ERβ. Mouse and human single-cell RNA sequencing (scRNA seq) data were analyzed to identify the subpopulation for ERα and ERβ expression. The expression of ERs was correlated to SRD5A2 expression with RNA sequencing (RNA seq) data from GTEx (Genotype-Tissue Expression, n=100) in normal prostate and TCGA (The Cancer Genome Atlas, n=496) databases for prostate cancer. Human prostatic stromal cell line (BHPrS1) and epithelial cell line (BPH1) were transfected with SRD5A2 plasmid or vector to identify the change of transcript and protein levels of SRD5A2, ERα, and ERβ. RESULTS: ERα and ERβ variably expressed in both the stroma and epithelium compartments of BPH surgical samples and had nucleus expression in human prostatic cell lines. ScRNA seq analysis of human and mouse prostate tissues showed that SRD5A2 is dominantly expressed in fibroblasts. Meanwhile, ERα expressed mainly in myofibroblasts of the human prostate and luminal cells of the mouse anterior prostate. ERβ had minimal expression both in mouse and human prostate. RNA seq analysis demonstrated a significant association between SRD5A2 and ERα in human benign and malignant prostate tissue. The transcript level of SRD5A2 was significantly positively correlated with ERα (R=0.6797, p=0.0019) and ERβ (R=0.7030, p=0.0011) in surgical specimens. In addition, in BHPrS1 cells, transcript and protein expressions of total ERα and phosphorylated ERα were upregulated in SRD5A2 overexpressed cells compared with vector control. CONCLUSIONS: Our study demonstrates that the expression of ERα is associated with SRD5A2 expression. Targeting the estrogenic signaling pathway may serve as an effective treatment strategy in 5ARI-insensitive BPH patients.
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