title: Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.
abstract: BACKGROUND
  Wnt/β-catenin signaling is important for prostate development and cancer in humans. Activation of this pathway in differentiated luminal cells of mice induces high-grade prostate intraepithelial neoplasia (HGPIN). Though the cell of origin of prostate cancer has yet to be conclusively identified, a castration-resistant Nkx3.1-expressing cell (CARN) may act as a cell of origin for prostate cancer.
  
  
  METHODS
  To activate Wnt/β-catenin signaling in CARNs, we crossed mice carrying tamoxifen-inducible Nkx3.1-driven Cre to mice containing loxP sites in order to either conditionally knock out adenomatous polyposis coli (Apc) or constitutively activate β-catenin directly. We then castrated and hormonally regenerated these mice to target the CARN population.
  
  
  RESULTS
  Loss of Apc in hormonally normal mice induced HGPIN; however, after one or more rounds of castration and hormonal regeneration, Apc-null CARNs disappeared. Alternatively, when β-catenin was constitutively activated under the same conditions, HGPIN was apparent.
  
  
  CONCLUSIONS
  Activation of Wnt/β-catenin signaling via Apc deletion is sufficient to produce HGPIN in hormonally normal mice. Loss of Apc may destabilize the CARN population under regeneration conditions. When β-catenin is constitutively activated, HGPIN occurs in hormonally regenerated mice. A second genetic hit is likely required to cause progression to carcinoma and metastasis.
authors.affiliation: Center for Skeletal Disease & Tumor Metastasis, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Valkenburg
authors.forename: Xiuping
authors.initials: X
authors.lastname: Yu
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Spiering
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D002369:Castration; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D011467:Prostate / Q000378:metabolism*; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D051176:beta Catenin; D013629:Tamoxifen
keywords: Apc; CARNs; Nkx3.1; Wnt; beta-catenin; mouse model