Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia

Kenneth C. Valkenburg, Xiuping Yu, Angelo Michael Demarzo, Tyler J. Spiering, Robert J. Matusik, Bart O. Williams

Research output: Contribution to journalArticlepeer-review

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.

CONCLUSION: 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.

Original languageEnglish (US)
Pages (from-to)1506-1520
Number of pages15
JournalThe Prostate
Volume74
Issue number15
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Keywords

  • Apc
  • beta-catenin
  • CARNs
  • mouse model
  • Nkx3.1
  • Wnt

ASJC Scopus subject areas

  • Oncology
  • Urology

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