title: PIK3CA and APC mutations are synergistic in the development of intestinal cancers.
abstract: Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Deming
authors.affiliation: Department of Oncology, University of Wisconsin, Madison, WI, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Leystra
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Nettekoven
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sievers
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Miller
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Middlebrooks
authors.affiliation: Department of Oncology, University of Wisconsin, Madison, WI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Clipson
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Promega Corporation, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bacher
authors.affiliation: Department of Pathology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Radiology, University of Wisconsin, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Weichert
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053842:Microsatellite Instability; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D058534:Class I Phosphatidylinositol 3-Kinases; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; C546639:Pik3ca protein, mouse