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

• Published in: The Prostate Vol. 74; no. 15; pp. 1506 - 1520
• Main Authors: Valkenburg, Kenneth C., Yu, Xiuping, De Marzo, Angelo M., Spiering, Tyler J., Matusik, Robert J., Williams, Bart O.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2014
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Animals; Apc; beta Catenin - metabolism; beta-catenin; CARNs; Castration; Enzyme-Linked Immunosorbent Assay; Epithelial Cells - metabolism; Immunohistochemistry; Male; Mice; mouse model; Nkx3.1; Prostate - metabolism; Prostatic Intraepithelial Neoplasia - metabolism; Prostatic Neoplasms - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen - pharmacology; Wnt; Wnt Proteins - metabolism; Wnt Signaling Pathway; beta-catenin; mouse model; Wnt; Apc; Nkx3.1; CARNs
• ISSN: 0270-4137; 1097-0045
• 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. Prostate 74:1506–1520, 2014. © 2014 Wiley Periodicals, Inc.