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Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K. PLoS One 2016;11(2):e0148730



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Pubmed Central ID




Scopus ID

2-s2.0-84959378791 (requires institutional sign-in at Scopus site)   15 Citations


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.

Author List

Yueh AE, Payne SN, Leystra AA, Van De Hey DR, Foley TM, Pasch CA, Clipson L, Matkowskyj KA, Deming DA


Dana Van De Hey Physician Assistant in the Neurology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Class I Phosphatidylinositol 3-Kinases
Colonic Neoplasms
Drug Screening Assays, Antitumor
Genetic Association Studies
Genetic Predisposition to Disease
Mice, Inbred C57BL
Mice, Transgenic
Mutation, Missense
Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Tumor Burden