title: Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/β-catenin/TCF-4 complex inhibition of c-MYC transcription.
abstract: BACKGROUND
  Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs).
  
  
  METHODS
  Lentiviral shRNA stable knock down of c-MYC, β-catenin, or TCF-4 completely inhibits normal (i.e., non-transformed) human PrECs growth. c-MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent β-catenin signaling either by blocking TCF-4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear β-catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor-I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor-I is overcome by constitutive c-MYC transcription.
  
  
  RESULTS
  In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c-MYC transcription, resulting in G0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen-induced formation of AR/β-catenin/TCF-4 complexes, which suppress c-MYC transcription. Such suppression does not occur when AR is mutated in its zinc-finger binding domain.
  
  
  CONCLUSIONS
  Proliferation of non-transformed human PrECs is dependent upon c-MYC transcription via formation/binding of β-catenin/TCF-4 complexes at both 5' and 3' c-MYC enhancers stimulated by Wnt-independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen-induced formation of AR/β-catenin/TCF-4 complexes, which retains binding to 3' c-MYC enhancer, but now suppresses c-MYC transcription.
authors.affiliation: Chemical Therapeutics Program and Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; Department of Urology, The Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Lizamma
authors.initials: L
authors.lastname: Antony
authors.forename: Freek
authors.initials: F
authors.lastname: van der Schoor
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D011467:Prostate / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C501126:DKK1 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt
keywords: TCF-4; androgen receptor; c-MYC, β-catenin; human prostate epithelial cells