c-erbB-2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells.
Separate mechanisms for oncogenesis and metastasis have been postulated. We show here that prolonged and invasive cell migration, a key mechanism in cancer metastasis, is linked to c-erbB-2 signaling. Cell lines with c-erbB-2 and EGFR expression and transphosphorylation activity display a high transendothelial invasiveness in an endothelial-extracellular matrix model mimicking a capillary vessel wall in vitro. Tyrosine-phosphorylated c-erbB-2 receptors and EGFR are localized predominantly in areas of the cell with high membrane extension activity. On the molecular level, there is a subtle cross talk between the transmembrane signaling molecule c-erbB-2 and the actin cytoskeleton at multiple levels, including the generation of the second messenger PIP2 and the mobilization of the actin-regulatory protein gelsolin. Our data strongly suggest that c-erbB-2, especially in a heterodimer with EGFR, is closely involved in signaling pathways, inducing alterations in cell morphology that are required for a human breast cancer cell to become motile and conceivably metastatic.
Brandt
B H
BH
Institut für Klinische Chemie und Laboratoriumsmedizin, 48149 Münster, Germany Institut für Immunologie, Universität Witten/Herdecke, Witten 58453, Germany. brandt@uni-muenster.de
Roetger
A
A
Dittmar
T
T
Nikolai
G
G
Seeling
M
M
Merschjann
A
A
Nofer
J R
JR
Dehmer-Möller
G
G
Junker
R
R
Assmann
G
G
Zaenker
K S
KS
D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division; D002460:Cell Line; D019281:Dimerization; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D018260:Gelsolin / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018260:Gelsolin; D018719:Erb-b2 Receptor Tyrosine Kinases