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Obesity Reawakens Prostatic Stem-like Features to Drive Prostate Volume Expansion and Attenuates 5ARI Effectiveness
Xingbo Long, M.D., Christina Sharkey, M.S., Yao Tang, M.S., Zongwei Wang, Ph.D., Aria F Olumi, M.D..
Beth Israel Deaconess Medical Center, Brookline, MA, USA.
BACKGROUND:Steroid 5α-reductase type 2 (SRD5A2) is a key enzyme involved in dihydrotestosterone (DHT)-driven prostate growth. While 5α-reductase inhibitors (5ARIs) are effective in treating benign prostatic hyperplasia (BPH) by suppressing DHT production, the impact of obesity, particularly dynamic changes in body mass index (BMI), on prostate enlargement and its interaction with 5ARI therapy remains poorly understood. Here, we aimed to investigate whether obesity is associated with BPH development and to determine the role of SRD5A2 expression in this process.
METHODS:Srd5a2-null and wild-type (WT) control mice were fed either a regular-fat diet (RFD) or a high-fat diet (HFD) for 3 months. Mouse prostate tissue was digested for single-cell RNA sequencing (scRNA-seq) and subjected to immunofluorescence (IF) staining to validate key findings. Additionally, RNA-seq data from 202 prostate biopsies in the Medical Therapy of Prostatic Symptoms (MTOPS) cohort were analyzed.
RESULTS:HFD induced significant prostatic hyperplasia in both WT and
Srd5a2-null mice.
HFD reactivated stem-like properties and increased the population of Trop2-positive cells in the proximal prostate, accompanied by aberrant epithelial lineage differentiation- effects were further exacerbated in
Srd5a2-null mice. Analysis of MTOPS cohort revealed a significant correlation between BMI change (ΔBMI) and enrichment of stemness signatures (r=0.38, p<0.001), along with a decline in lineage differentiation signatures, particularly among patients treated with 5ARI. ΔBMI independently predicted prostate volume expansion (β=0.95, p=0.04), with the most pronounced effects observed in the transition zone (β=0.99, p=0.04). Notably, patients with ΔBMI > 2.05 kg/mē exhibited a significantly diminished therapeutic response to 5ARI treatment.
CONCLUSIONS:These findings suggest that obesity promotes prostate enlargement by reactivating stem-like properties and impairing epithelial differentiation, independent of SRD5A2 expression. Longitudinal increases in BMI are associated with reduced responsiveness to 5ARI therapy, identifying obesity as a potential modifier of BPH progression and treatment outcomes.
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