ESR1+ luminal epithelial cells contribute to androgen-independent prostate survival in the absence of SRD5A2
Steroid 5a reductase 2 (SRD5A2) is crucial for prostatic development, converting testosterone to dihydrotestosterone (DHT). While 5a reductase inhibitors (5ARI) effectively reduce prostate size in benign prostate hyperplasia (BPH), their limited efficacy against BPH-related lower urinary tract symptoms (LUTS) and mechanisms of 5ARI resistance remain unclear. Here, we developed a Srd5a2-/- mouse model and employed single-cell RNA sequencing (scRNA-seq) to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial (LE) populations were observed, alongside increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)+ Luminal Epithelia 2 (LE2) cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting alternative pathways for prostate growth without SRD5A2. Human prostate biopsy analysis revealed an inverse correlation between SRD5A2 expression and LE2 markers (ESR1 and PKCa). These findings provide insights into prostate biology, 5ARI resistance mechanisms, and potential targeted therapies for BPH-related LUTS. Overall design: Single-cell sequencing was performed on three fresh prostate tissues, including one from Srd5a2-/- mice and two from Srd5a2+/- mice.