title: Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations.
abstract: An oncogenic mutation (G49A:E17K) in the AKT1 gene has been described recently in human breast, colon, and ovarian cancers. The low frequency of this mutation and perhaps other selective pressures have prevented the isolation of human cancer cell lines that harbor this mutation thereby limiting functional analysis. Here, we create a physiologic in vitro model to study the effects of this mutation by using somatic cell gene targeting using the nontumorigenic human breast epithelial cell line, MCF10A. Surprisingly, knock in of E17K into the AKT1 gene had minimal phenotypic consequences and importantly, did not recapitulate the biochemical and growth characteristics seen with somatic cell knock in of PIK3CA hotspot mutations. These results suggest that mutations in critical genes within the PI3-kinase (PI3K) pathway are not functionally equivalent, and that other cooperative genetic events may be necessary to achieve oncogenic PI3K pathway activation in cancers that contain the AKT1 E17K mutation.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. jlaurin1@jhmi.edu
authors.forename: J
authors.initials: J
authors.lastname: Lauring
authors.forename: D P
authors.initials: DP
authors.lastname: Cosgrove
authors.forename: S
authors.initials: S
authors.lastname: Fontana
authors.forename: J P
authors.initials: JP
authors.lastname: Gustin
authors.forename: H
authors.initials: H
authors.lastname: Konishi
authors.forename: A M
authors.initials: AM
authors.lastname: Abukhdeir
authors.forename: J P
authors.initials: JP
authors.lastname: Garay
authors.forename: M
authors.initials: M
authors.lastname: Mohseni
authors.forename: G M
authors.initials: GM
authors.lastname: Wang
authors.forename: M J
authors.initials: MJ
authors.lastname: Higgins
authors.forename: D
authors.initials: D
authors.lastname: Gorkin
authors.forename: M
authors.initials: M
authors.lastname: Reis
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
authors.forename: K
authors.initials: K
authors.lastname: Polyak
authors.forename: M
authors.initials: M
authors.lastname: Cowherd
authors.forename: P J
authors.initials: PJ
authors.lastname: Buckhaults
authors.forename: B H
authors.initials: BH
authors.lastname: Park
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494918:AKT1 protein, human