title: Motility enhancement by tumor-derived mutant E-cadherin is sensitive to treatment with epidermal growth factor receptor and phosphatidylinositol 3-kinase inhibitors.
abstract: Diffuse-type gastric and lobular breast cancers are characterized by frequent mutations in the cell adhesion molecule E-cadherin. Here we report that tumor-associated mutations of E-cadherin enhanced random cell movement of transfected MDA-MB-435S mammary carcinoma cells as compared to wild-type (wt) E-cadherin-expressing cells. The mutations included in frame deletions of exons 8 or 9 and a point mutation in exon 8 which all affect putative calcium-binding sites within the linker region of the second and third extracellular domain. Motility enhancement by mutant E-cadherin was investigated by time-lapse laser scanning microscopy. Increased cell motility stimulated by mutant E-cadherin was influenced by cell-matrix interactions. The motility-increasing activity of mutant E-cadherin was blocked by application of pharmacological inhibitors of epidermal growth factor receptor and phosphatidylinositol (PI) 3-kinase. Investigation of the activation status of PI 3-kinase and the downstream signaling molecules Akt/protein kinase B and MAP kinase p44/42 showed that these kinases are not more strongly activated in mutant E-cadherin-expressing cells than in wt E-cadherin-expressing cells. Instead, the basal level of PI 3-kinase is necessary for mutant E-cadherin-enhanced cell motility. Our data suggest a critical role of E-cadherin mutations for the fine tuning of tumor cell motility.
authors.affiliation: Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Munich, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Fuchs
authors.forename: Peter
authors.initials: P
authors.lastname: Hutzler
authors.forename: Ingrid
authors.initials: I
authors.lastname: Brunner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlegel
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.forename: Ute
authors.initials: U
authors.lastname: Reuning
authors.forename: Sandra
authors.initials: S
authors.lastname: Hapke
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Genda
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Florian
authors.initials: F
authors.lastname: Uberall
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Becker
authors.forename: Birgit
authors.initials: B
authors.lastname: Luber
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017354:Point Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human