title: β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors.
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-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.
authors: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, USA. peter.clark@vanderbilt.edu
authors: Peter E
authors: PE
authors: Clark
authors: Dina
authors: D
authors: Polosukhina
authors: Harold
authors: H
authors: Love
authors: Hernan
authors: H
authors: Correa
authors: Cheryl
authors: C
authors: Coffin
authors: Elizabeth J
authors: EJ
authors: Perlman
authors: Mark
authors: M
authors: de Caestecker
authors: Harold L
authors: HL
authors: Moses
authors: Roy
authors: R
authors: Zent
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D005091:Exons / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051762:PAX2 Transcription Factor / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000077022:Survivin; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; C551916:CTNNBL1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; D012097:Repressor Proteins; D000077022:Survivin; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase