title: Loss of the ceramide transfer protein augments EGF receptor signaling in breast cancer.
abstract: Triple-negative breast cancers (TNBC) are especially refractory to treatment due to their negative hormone receptor and ErbB2/HER2 status. Therefore, the identification of cancer-associated deregulated signaling pathways is necessary to develop improved targeted therapies. Here, we show that expression of the ceramide transfer protein CERT is reduced in TNBCs. CERT transfers ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin (SM). We provide evidence that by regulating cellular SM levels, CERT determines the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in approximately 70% of TNBCs. CERT downregulation in breast cancer cells enhanced ErbB1 lateral mobility, ligand-induced autophosphorylation, internalization, and chemotaxis. Together, our findings provide a link between lipid metabolism at the Golgi with signaling at the plasma membrane, thereby implicating CERT loss in the progression of TNBCs.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Heering
authors.forename: Nicole
authors.initials: N
authors.lastname: Weis
authors.forename: Monika
authors.initials: M
authors.lastname: Holeiter
authors.forename: Felix
authors.initials: F
authors.lastname: Neugart
authors.forename: Annette
authors.initials: A
authors.lastname: Staebler
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Fehm
authors.forename: Annabell
authors.initials: A
authors.lastname: Bischoff
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schiller
authors.forename: Stephan
authors.initials: S
authors.lastname: Duss
authors.forename: Simone
authors.initials: S
authors.lastname: Schmid
authors.forename: Thomas
authors.initials: T
authors.lastname: Korte
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Monilola A
authors.initials: MA
authors.lastname: Olayioye
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D022001:Focal Adhesions; D006801:Humans; D010739:Phospholipase D / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C119090:CERT1 protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C105606:phospholipase D2; D010739:Phospholipase D