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

Valkenburg KC, Yu X, De Marzo AM, Spiering TJ, Matusik RJ, Williams BO
Prostate. 2014 74 (15): 1506-20

PMID: 25175604 · PMCID: PMC4175140 · DOI:10.1002/pros.22868

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.

© 2014 Wiley Periodicals, Inc.

MeSH Terms (16)

Adenomatous Polyposis Coli Protein Animals beta Catenin Castration Enzyme-Linked Immunosorbent Assay Epithelial Cells Immunohistochemistry Male Mice Prostate Prostatic Intraepithelial Neoplasia Prostatic Neoplasms Reverse Transcriptase Polymerase Chain Reaction Tamoxifen Wnt Proteins Wnt Signaling Pathway

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