title: Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes.
abstract: Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable.
  
  
  
  Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts.
  
  
  
  A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s).
  
  
  
  Regulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome.
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway. Jan.R.Olsen@uib.no.|, Laboratory Bld. 5. etg, Bergen Health, Bergen, NO-5021, Norway. Jan.R.Olsen@uib.no.
authors.forename: Jan Roger
authors.identifier: 0000-0001-6547-431X
authors.initials: JR
authors.lastname: Olsen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
authors.forename: Waqas
authors.initials: W
authors.lastname: Azeem
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Margrete Reime
authors.initials: MR
authors.lastname: Hellem
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Kristo
authors.initials: K
authors.lastname: Marvyin
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Cancer Institute, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Institute, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Department of Urology, University of Washington, Seattle, WA, USA.
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Xi- Song
authors.initials: X
authors.lastname: Ke
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Anne Margrete
authors.initials: AM
authors.lastname: Øyan
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway. Kalland@uib.no.|Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway. Kalland@uib.no.|Department of Microbiology, Haukeland University Hospital, Bergen, Norway. Kalland@uib.no.|, Laboratory Bld. 5. etg, Bergen Health, Bergen, NO-5021, Norway. Kalland@uib.no.
authors.forename: Karl- Henning
authors.initials: K
authors.lastname: Kalland
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D017423:Sequence Analysis, RNA / Q000379:methods; D059010:Single-Cell Analysis
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen
keywords: Androgen receptor; Differentiation; Epithelial to mesenchymal transition; Human prostate cancer; Stem cell