Chronic inflammation is a well-established feature of BPH. In this Center proposal, we show that activation of the NF-?B pathway, a response to inflammation is associated with increased prostatic volume and therapeutic failure in symptomatic BPH. We also show that NF-?B activation leads to the expression of an AR variant isoform, AR-V7, which lacks a ligand binding domain of the AR. Furthermore, we show that BPH patients who no longer respond to treatment have greater NF-?B activation and AR-V7 expression in the prostate transition zone compared to incidental BPH patients, consistent with a loss of sensitivity to 5?-reductase inhibitors (5ARI). Similarly, 5ARI therapy appears less effective among obese patients consistent with chronic systemic inflammation, and NF-?B activation. The goal of this Center is to determine the pathways linking obesity, inflammation, NF-?B activity, and AR-V induction driving BPH progression and drug therapy failure. We propose three interlinked projects to determine the consequences of inflammation and NF-?B activation. The first project utilizes tissue and data from the Medical Therapy of Prostatic Symptoms (MTOPS) clinical trial to identify changes in NF-?B, IL-6, and AR-V activity over time in the prostate transition zone and the association with BPH progression and response to therapy. The second project uses our human BPH tissue repository for an expansive investigation of the links between inflammatory macrophages and disease progression, then utilizes xenograft models to interrogate the specific roles of NF-?B, AR-V and obesity in BPH resistance to 5ARI therapy. The third project is a detailed investigation of the molecular mechanisms underlying the interactions between AR function, AR-V expression and the activity of NF-?B and 5?-reductase in human prostatic cells. The Center's Tissue and Data Biorepository and Administrative Cores play critical roles in these investigations, including tissu acquisition, histopathologic assessment, data management, and biostatistical and bioinformatic analysis. Importantly, we will bring novel resources and expertise to the NIDDK program, including extensive RNA-seq data from the MTOPS trial samples and a large and growing human BPH tissue repository with linked patient data to enable the future exploration of novel hypotheses as they develop. The Center will also support an Educational Enrichment program that will provide instruction and connections to the research community and training opportunities to students at the undergraduate and medical school levels.
Benign prostatic hyperplasia is a major public health issue with significant morbidity and associated public healthcare costs. This Center will focus on the issue of therapy resistance in BPH patients with a view to understanding and reversing this process to render patients more responsive to medical therapies. Resources generated in this center will also help accelerate collaborative BPH research across the country.
| Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-?B and androgen receptor variant expression correlate with human BPH progression. Prostate 76:491-511 |
| Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-?B and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance. Prostate 76:1004-18 |
