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

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $402,692

## Abstract

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.

## Key facts

- **NIH application ID:** 9990757
- **Project number:** 5R01DK111554-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** ROBERT J. MATUSIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,692
- **Award type:** 5
- **Project period:** 2016-09-16 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990757

## Citation

> US National Institutes of Health, RePORTER application 9990757, The NF-KappaB-Androgen Receptor Axis Drives Failure of Medical Therapy in Human Benign Prostatic Hyperplasia (5R01DK111554-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9990757. Licensed CC0.

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