title: Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.
abstract: The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling.
authors: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
authors: Alexander E
authors: AE
authors: Yueh
authors: University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.
authors: Susan N
authors: SN
authors: Payne
authors: Department of Oncology, University of Wisconsin Madison, Madison, WI, United States of America.
authors: Alyssa A
authors: AA
authors: Leystra
authors: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
authors: Dana R
authors: DR
authors: Van De Hey
authors: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
authors: Tyler M
authors: TM
authors: Foley
authors: University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.
authors: Cheri A
authors: CA
authors: Pasch
authors: Department of Oncology, University of Wisconsin Madison, Madison, WI, United States of America.
authors: Linda
authors: L
authors: Clipson
authors: University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.|Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.|William S Middleton Memorial Veterans Hospital, Madison, WI, United States of America.
authors: Kristina A
authors: KA
authors: Matkowskyj
authors: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.|University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.|William S Middleton Memorial Veterans Hospital, Madison, WI, United States of America.
authors: Dustin A
authors: DA
authors: Deming
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C546639:Pik3ca protein, mouse; C531198:dactolisib