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

Clark PE, Polosukhina D, Love H, Correa H, Coffin C, Perlman EJ, de Caestecker M, Moses HL, Zent R
Am J Pathol. 2011 179 (6): 3045-55

PMID: 21983638 · PMCID: PMC3260797 · DOI:10.1016/j.ajpath.2011.08.006

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-catenin-dependent 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-kinase-AKT and extracellular signal-regulated 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.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (24)

Animals Apoptosis Regulatory Proteins beta Catenin Cell Transformation, Neoplastic Exons Genes, ras Humans Inhibitor of Apoptosis Proteins Kidney Neoplasms Kidney Tubules, Proximal MAP Kinase Signaling System Mice Mice, Transgenic Mutation Nuclear Proteins Paired Box Transcription Factors PAX2 Transcription Factor PAX8 Transcription Factor Phosphatidylinositol 3-Kinase Phosphatidylinositol 3-Kinases Repressor Proteins Signal Transduction Survivin Wilms Tumor

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