The NF-KappaB-Androgen Receptor Axis Drives Failure of Medical Therapy in Human Benign Prostatic Hyperplasia

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PROJECT SUMMARY With the exception of increasing age and dysregulated androgen activity, little is known on how BPH develops and why patients respond very differently to existing drugs. Steroid 5α-reductase inhibitors (5ARI) block the conversion of testosterone (T) to dihydrotestosterone (DHT), representing a major therapy for shrinking prostate volume in approximately 34% of symptomatic BPH patients. Our data suggest a fundamental mechanism underlying the resistance of BPH to 5ARIs. We show that nuclear factor kappa B (NFκB) mediates induction of Androgen Receptor Variant 7 (AR-V7), an AR isoform that lacks the Ligand Binding Domain (LBD) of the full-length AR (AR-FL), resulting in constitutively active AR signaling even in the absence of DHT. We demonstrate for the first time that severely symptomatic BPH patients express AR-Vs, and that NFκB regulates the expression of AR-FL and AR-V7 mRNA in spontaneously immortalized human benign prostatic cells. Further, expression of NFκB or AR-V7 in benign prostatic cells is sufficient to induce resistance to 5ARI treatment. Also, we show that NFκB and AR-V7 up-regulate steroid-5α-reductase type II (SRD5A2) expression. Consistent with our cell culture experiments, we show that BPH patient samples have elevated levels of NFκB, AR-V7, and SRD5A2 expression. We demonstrate that AR-V7 and SRD5A2 expression significantly correlated with the Transrectal ultrasound (TRUS) prostatic volume and American Urological Association Symptom Scores (AUASS) in BPH patients, measures of the patients' severity of lower urinary tract symptoms (LUTS). This data suggests a BPH model where a loop of self-reliance develops to overcome medical therapy that is triggered by NFκB and AR-V7 to raise SRD5A2 levels and the production of DHT to re- initiate AR-FL activity. Our Hypothesis is that NFκB and AR signaling controls the failed response to 5ARIs in BPH. To unravel the mechanism of failure of 5ARI, we propose three Specific Aims: 1) To determine cross-talk between NFκB and AR signaling to regulate failure of medical therapy; 2) To determine the SRD5A isoforms contribution during resistance to medical therapy; and 3) To determine if failure of medical therapy is driven by NFκB and/or AR-V7 in BPH patients. These aims will use molecular approaches, measurements of androgens and 5ARI levels and gene expression in BPH tissue, and 3D organoid cultures from BPH patients to test the mechanism of failure to 5ARI therapy. Our model may provide a general mechanism explaining failure of medical therapy or it may identify a subpopulation of BPH patients which could point the way towards precision medicine that would personalize care for these patients.