title: NF-κB and androgen receptor variant expression correlate with human BPH progression.
abstract: BACKGROUND
  Benign prostatic hyperplasia (BPH) is a common, chronic progressive 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.
  
  
  METHODS
  NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. 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. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed.
  
  
  RESULTS
  Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. 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.
  
  
  CONCLUSIONS
  Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: David C
authors.initials: DC
authors.lastname: Austin
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Strand
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Love
authors.affiliation: Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, Illinois.
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Alex
authors.initials: A
authors.lastname: Jang
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Grabowska
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Miller
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Omar
authors.initials: O
authors.lastname: Hameed
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Fowke
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ren J
authors.initials: RJ
authors.lastname: Jin
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, Illinois.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016328:NF-kappa B; D011944:Receptors, Androgen
keywords: BPH; Inflammation; NF-κB; androgen receptor; androgen receptor variant 7