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: Margit Fuchs, Peter Hutzler, Ingrid Brunner, Jürgen Schlegel, Jörg Mages, Ute Reuning, Sandra Hapke, Justus Duyster, Setsuo Hirohashi, Takuya Genda, Michiie Sakamoto, Florian Uberall, Heinz Höfler, Karl-Friedrich Becker, Birgit Luber
• Journal: Experimental cell research (Exp Cell Res) Vol. 276 Issue 2 Pg. 129-41 (Jun 10 2002) ISSN: 0014-4827 [Print] United States
• PMID: 12027444 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2002 Elsevier Science (USA).

Chemical References

• Cadherins
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• ErbB Receptors
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Breast Neoplasms (enzymology, genetics, physiopathology)
• Cadherins (genetics, metabolism)
• Carcinoma (enzymology, genetics, physiopathology)
• Cell Adhesion (genetics)
• Cell Movement (drug effects, genetics)
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Extracellular Matrix (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• MAP Kinase Signaling System (genetics)
• Neoplasm Invasiveness (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Point Mutation (genetics)
• Protein Serine-Threonine Kinases
• Protein Structure, Tertiary (genetics)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt
• Tumor Cells, Cultured