Cancer-specific mutations in PIK3CA are oncogenic in vivo.
The PIK3CA gene, coding for the catalytic subunit p110alpha of class IA phosphatidylinositol 3-kinases (PI3Ks), is frequently mutated in human cancer. Mutated p110alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.
Bader
Andreas G
AG
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kang
Sohye
S
Vogt
Peter K
PK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D006394:Hemangiosarcoma / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010919:Placebos; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000970:Antineoplastic Agents; D010919:Placebos; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020123:Sirolimus