Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation

Cancer Res. 2013 Jun 1;73(11):3248-61. doi: 10.1158/0008-5472.CAN-12-1578. Epub 2013 Apr 11.

Abstract

The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Growth Processes / physiology
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Class I Phosphatidylinositol 3-Kinases
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Female
  • Gene Knock-In Techniques
  • Heterografts
  • Humans
  • Immunocompromised Host
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Point Mutation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • KRAS protein, human
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Proto-Oncogene Proteins
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins