Stromal SRD5A2 promotes prostate growth through WNT5A-LEF1-IGF1 signaling in benign prostatic hyperplasia

Steroid 5 alpha-reductase type 2 (SRD5A2) is a key enzyme in androgen metabolism and a pharmacologic target in benign prostatic hyperplasia (BPH). While SRD5A2 is known to mediate stromal-epithelial interactions that influence prostate growth, the relationship between baseline SRD5A2 expression and prostate volume remains unclear. In this study, we analyzed SRD5A2 expression in human prostate tissues from the Medical Therapy of Prostatic Symptoms (MTOPS) trial and institutional biorepository cohorts. Quantitative assessments were performed and correlations were evaluated between expression level of SRD5A2, WNT5A, prostate volume, and tissue signaling profiles. SRD5A2 expression was significantly associated with total prostate and transition zone volume. Stromal-specific WNT5A expression showed a strong positive correlation with SRD5A2, while neither serum nor tissue dihydrotestosterone levels correlated with SRD5A2 expression. In Srd5a2-null mice, Wnt5a expression in the prostate stroma was dependent on Srd5a2 and showed region-specific regulation. Mechanistically, SRD5A2 overexpression in human prostate stromal cells upregulated WNT5A and Lymphoid Enhancer-Binding Factor 1 (LEF1), activated insulin-like growth factor 1 (IGF1) signaling, increased proliferation, and reduced apoptosis. Conditioned media from these cells enhanced epithelial proliferation through paracrine IGF1 activity. This study provides the first evidence that SRD5A2 promotes prostate growth through a stromal WNT5A-LEF1-IGF1 paracrine signaling axis independent of androgen levels, suggesting a novel therapeutic mechanism relevant for BPH patients with resistance to conventional 5 alpha-reductase inhibitor therapy. Generation of Srd5a2-null (Srd5a2-/-) and heterozygous (Srd5a2+/–) mice model was previously described (Sharkey et al. 2024). Male Srd5a2+/- (Het) were crossed with wild-type (WT) C57BL6 female mice. The offspring of these heterozygous mice were bred further to obtain one-quarter of Srd5a2-null (KO) male offspring from the third generation. Prostate was harvest from WT, HET and KO mice. Total RNA was extracted from prostate tissue and sent for bulk RNA sequencing.