title: Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation.
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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of , The Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wang
authors.forename: Hong Yuen
authors.initials: HY
authors.lastname: Wong
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Brian G
authors.initials: BG
authors.lastname: Blair
authors.forename: Abde M
authors.initials: AM
authors.lastname: Abukhdeir
authors.forename: John P
authors.initials: JP
authors.lastname: Gustin
authors.forename: D Marc
authors.initials: DM
authors.lastname: Rosen
authors.forename: Samuel Ray
authors.initials: SR
authors.lastname: Denmeade
authors.forename: Zeshaan
authors.initials: Z
authors.lastname: Rasheed
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garay
authors.forename: Morassa
authors.initials: M
authors.lastname: Mohseni
authors.forename: Michaela J
authors.initials: MJ
authors.lastname: Higgins
authors.forename: Justin
authors.initials: J
authors.lastname: Cidado
authors.forename: Danijela
authors.initials: D
authors.lastname: Jelovac
authors.forename: Sarah
authors.initials: S
authors.lastname: Croessmann
authors.forename: Rory L
authors.initials: RL
authors.lastname: Cochran
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055879:Gene Knock-In Techniques; D064593:Heterografts; D006801:Humans; D016867:Immunocompromised Host; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D018631:ras Proteins; C117307:KRAS protein, human; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C484760:PIK3CA protein, human