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David Austin, Ph.D.

Department: Cancer Biology, 2016

Faculty Mentor: Simon Hayward, Ph.D.

Dissertation Title: The Role of Nuclear Factor Kappa B in Benign Prostatic Hyperplasia

Dissertation Abstract: Benign prostatic hyperplasia (BPH) is a common, progressive chronic disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression. Most patients initially respond to 5ARI therapy; however, failure is common. To address why patients fail therapy we used transition zone tissue samples from patients with a wide range of American Urological Association symptom score (AUASS) from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. NF-κB activation and androgen receptor variant (AR-V) expression were quantified. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity, AR-FL, and AR-variant 7 (AR-V7). We determined that canonical NF-κB signaling was found to be upregulated in late versus early stage BPH. Elevated expression of AR-V7 was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. To understand why NF-κB and AR-V7 maintained viability within 5ARI treatment we examined the levels of 5α-reductase enzymes (SRD5A1, SRD5A2, SRD5A3). We determined that SRD5A2 is upregulated in more advanced BPH. SRD5A2 was significantly associated with AUASS and patients on a 5ARI. AR-FL and AR-V7 expression increased SRD5A2 expression whereas forced NF-κB activation increased all SRD5A isoforms. In summary, activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. Increased BPH severity in patients correlates with SRD5A2 expression. De novo synthesis of androgens and AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB. NF-κB and AR-V7 upregulate SRD5A2 resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy.