Decreased SRD5A2 and Alternative Estrogen Signaling in Prostatic Cell Survival

PROJECT SUMMARY Benign prostatic hyperplasia (BPH) remains a significant and incurable health problem that will become more prevalent as life expectancy increases. Despite the introduction of steroid 5α-reductase inhibitors (5ARI) through inhibiting the conversion of testosterone to dihydrotestosterone (DHT) to manage BPH and associated lower urinary tract symptoms (LUTS), progression of LUTS was only slowed by 34% with 5ARI-response. Therefore, the utilization of 5ARI remains ineffective in many patients, leading to the use of invasive therapies. Here we propose to study the mechanisms of non-responsiveness to 5ARI. Ongoing work in our lab has focused on steroid 5α-reductase 2 (SRD5A2), the enzyme responsible for prostatic development and growth. We have revealed that the expression of SRD5A2 is variable; in fact, 30% of men do not express SRD5A2 in prostate tissues. Our studies indicate that the epigenetic silencing of SRD5A2 promotes an androgenic-to-estrogenic switch in epithelial cell transcriptional regulation. To investigate the underlying mechanism of prostate cells’ response to the restriction of DHT when SRD5A2 is low, we generated SRD5A2 null (SRD5A2-/-) mice. With single cell RNA sequencing (scRNA-Seq), we discovered a discrete subpopulation of luminal epithelial-2 (LE2) cells from the anterior prostate that has increased expression of estrogen receptor α (ERα, ESR1) and PKCα in the absence of SRD5A2. This subset may represent the emergence of an androgen-independent phenotype. Therefore, we hypothesize that ESR1+/PKCα+ LE2 cells acquire enhanced survival potential in the absence of SRD5A2, leading to androgen-independent prostatic survival. To identify the signaling that maintains LE2 cell and prostate survival upon DHT restriction, we propose the following specific aims: Aim 1 will elucidate that LE2 cells are the significant cell population resistant to SRD5A2 suppression. Aim 2 will define ER signaling that sustains the survival of LE2 cells in the absence of SRD5A2. Aim 3 will determine LE2 cells and ER signaling in the human prostate and their responsiveness to 5ARI therapy. Our findings have broad implications for using 5ARI for BPH management and may open new avenues for developing novel and alternate therapies.