dc.creator | Austin, David C. | |
dc.date.accessioned | 2020-08-21T21:12:49Z | |
dc.date.available | 2018-03-31 | |
dc.date.issued | 2016-03-31 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03172016-154256 | |
dc.identifier.uri | http://hdl.handle.net/1803/10843 | |
dc.description.abstract | Benign prostatic hyperplasia (BPH) is a common, progressive chronic disease. Inflammation is associated with prostatic enlargement and resistance to 5?-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-?B) 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-?B 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-?B activity, AR-FL, and AR-variant 7 (AR-V7). We determined that canonical NF-?B 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-?B 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-?B and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. To understand why NF-?B and AR-V7 maintained viability within 5ARI treatment we examined the levels of 5?-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-?B activation increased all SRD5A isoforms. In summary, activation of NF-?B 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-?B. NF-?B and AR-V7 upregulate SRD5A2 resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy. | |
dc.format.mimetype | application/pdf | |
dc.subject | Androgen Receptor Variant 7 | |
dc.subject | Inflammation | |
dc.subject | Androgen Receptor | |
dc.title | The Role of Nuclear Factor Kappa B in Benign Prostatic Hyperplasia | |
dc.type | dissertation | |
dc.contributor.committeeMember | Deborah Lannigan | |
dc.contributor.committeeMember | Simon Hayward | |
dc.contributor.committeeMember | Dineo Khabele | |
dc.contributor.committeeMember | Ann Richmond | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cancer Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2018-03-31 | |
local.embargo.lift | 2018-03-31 | |
dc.contributor.committeeChair | Fiona Yull | |