Aberrant expression and activation of EGFR and ERBB2 (HER2) have been 
successfully targeted for cancer therapeutics. Recent evidence from both basic 
and clinical studies suggests that ERBB3 (HER3) serves as a key activator of 
downstream signaling through dimerization with other ERBB proteins and plays a 
critical role in the widespread clinical resistance to EGFR and HER2 targeting 
cancer therapies. As a result, HER3 is actively pursued as an antibody 
therapeutic target for cancer. Ligand binding is thought to be a prerequisite 
for dimerization of HER3 with other ERBB proteins, which results in 
phosphorylation of its c-terminal tyrosine residues and activation of downstream 
AKT and MAPK signaling pathways. In this study, we report that an anti-HER2 
monoclonal antibody (HER2Mab), which blocks HER2 dimerization with HER3, induces 
HER3 dimerization with EGFR in both low and high HER2 expressing cancer cells. 
Treatment of the low HER2 expressing MCF7 cancer cells with HER2Mab promoted 
cell proliferation and migration in the absence of HER3 ligand stimulation. 
Follow-up studies revealed that HER2Mab-induced HER3 signaling via EGFR/HER3 
dimerization and activation of downstream AKT signaling pathways. These results 
suggest that equilibrium of dimerization among the ERBB proteins can be 
perturbed by HER2Mab and HER3 plays a key role in sensing the perturbation.