β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors

Peter E. Clark*, Dina Polosukhina, Harold Love, Hernan Correa, Cheryl Coffin, Elizabeth J. Perlman, Mark De Caestecker, Harold L. Moses, Roy Zent

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence of activated β-catenindependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing β-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, metastatic, multifocal primitive renal epithelial tumors that have the histologic and staining characteristics of the epithelial component of human WT. These highly malignant tumors have increased activation of the phosphatidylinositol 3-kinaseAKT and extracellular signalregulated kinase pathways, increased expression of total and nuclear β-catenin, and increased downstream targets of this pathway, such as c-Myc and survivin. Thus, we developed a novel mouse model in which activated K-RAS synergizes with canonical Wnt/β-catenin signaling to form metastatic primitive renal epithelial tumors that mimic the epithelial component of human WT.

Original languageEnglish (US)
Pages (from-to)3045-3055
Number of pages11
JournalAmerican Journal of Pathology
Volume179
Issue number6
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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