M. Egeblad et al., Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology, INT J CANC, 94(2), 2001, pp. 185-191
Shedding of the extracellular domain of the ErbB2 tyrosine kinase receptor
and expression of the remaining NH2-terminally truncated ErbB2 correlates w
ith lymph node metastases and adverse outcome in human breast cancer. To st
udy the possible signaling from such a truncated receptor, MCF-7 human brea
st cancer cells expressing NH2-terminally truncated ErbB2 (Delta NErbB2) we
re compared with cells overexpressing wild-type ErbB2. Expression of Delta
NErbB2 in MCF-7 cells resulted in sustained activation of extracellular sig
nal-regulated kinases (ERK) 1/2, extensive loss of the epithelial morpholog
y, appearance of vesicles and long protrusions as well as pronounced scatte
ring of the cells. Similar alterations were observed upon ErbB2 overexpress
ion but at much lower levels. Employing cell clones with inducible expressi
on of Delta NErbB2, it was revealed that the morphological changes were ful
ly reversible and depended on continuous expression of Delta NErbB2 but not
on the activation of the ERK 1/2 pathway. Interestingly, the expression of
Delta NErbB2 resulted also in the increased expression and phosphorylation
of ErbB 1 as well as in the prolonged ligand-induced activation of the Erb
B 1 signaling pathway. In conclusion, constitutive signaling upon expressio
n of the truncated ErbB2 receptor in human breast cancer cells promotes mor
phological changes indicative of a more motile and aggressive phenotype. (C
) 2001 Wiley-Liss, Inc.