c‐erbB‐2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells

ABSTRACTSeparate 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‐extra‐cellular 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., Roetger, A., Dittmar, T., Nikolai, G., Seeling, M., Merschjann, A., Nofer, J.‐R., Dehmer‐Möller, G., Junker, R., Assmann, G., Zaenker. K. S. c‐erbB‐2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. FASEB J. 13, 1939–1949 (1999)