title: Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.
abstract: Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Young
authors.affiliation: §Biochemistry, ‡‡Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Zimmerman
authors.affiliation: ¶Cancer Biology.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Ariella B
authors.initials: AB
authors.lastname: Hanker
authors.affiliation: ¶¶Departments of Pathology and Laboratory Medicine and Genetics; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gatza
authors.affiliation: ¶Cancer Biology.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Morrison
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Preston D
authors.initials: PD
authors.lastname: Moore
authors.affiliation: ‡‡Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Corbin A
authors.initials: CA
authors.lastname: Whitwell
authors.affiliation: §§Houston Methodist Cancer Center, Houston, Texas;
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.affiliation: ‖Pathology, Microbiology and Immunology; **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee;
authors.forename: Thomas
authors.initials: T
authors.lastname: Stricker
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bhola
authors.affiliation: ¶¶Departments of Pathology and Laboratory Medicine and Genetics; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Grace O
authors.initials: GO
authors.lastname: Silva
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Premal
authors.initials: P
authors.lastname: Patel
authors.affiliation: From the Departments of ‡Medicine.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
authors.affiliation: Baylor Charles A. Sammons Cancer Center, Dallas, Texas;
authors.forename: Maren
authors.initials: M
authors.lastname: Levin
authors.affiliation: Baylor Charles A. Sammons Cancer Center, Dallas, Texas;
authors.forename: Marina
authors.initials: M
authors.lastname: Horiates
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Palma
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: ¶¶Departments of Pathology and Laboratory Medicine and Genetics; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: ¶Cancer Biology, ‖Pathology, Microbiology and Immunology;
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
authors.affiliation: Baylor Charles A. Sammons Cancer Center, Dallas, Texas; Texas Oncology, US Oncology, Dallas, Texas;
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
authors.affiliation: §§Houston Methodist Cancer Center, Houston, Texas;
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: ‖‖The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.affiliation: §Biochemistry, ‡‡Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Liebler
authors.affiliation: ¶Cancer Biology, **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee;
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.affiliation: From the Departments of ‡Medicine, ¶Cancer Biology, **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; carlos.arteaga@vanderbilt.edu.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D066258:Amphiregulin / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002853:Chromatography, Liquid; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D066258:Amphiregulin; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases