ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors

ErbB-2/HER2 is an important signaling partner for the epidermal growth fact or receptor (EGFR), Overexpression of erbB-2 is also associated with poor p rognosis in breast cancer. To investigate how erbB-2 amplification affects its interactions with the EGFR, we used a human mammary epithelial cell sys tem in which erbB-2 expression was increased 7-20-fold by gene transfection . We found that amplification of erbB-2 caused constitutive activation of e rbB-2 as well as ligand-independent activation of the EGFR. Overexpression of erbB-2 strongly inhibited erbB-2 down-regulation following transactivati on by EGFR. Significantly, down-regulation of activated EGFR was also inhib ited by erbB-2 amplification, resulting in enhanced ligand-dependent activa tion of the EGFR. The rate of EGFR endocytosis was not affected by erbB-2 o verexpression, but the rate of lysosomal targeting was significantly reduce d. In addition, erbB-2 overexpression promoted rapid recycling of activated EGFR back to the cell surface and decreased ligand dissociation from the E GFR. Our data suggest that overexpression of erbB-2 inhibits both its downr egulation and that of the EGFR. The net effect is increased signaling throu gh the EGFR system.