Heregulin (
HRG) is an activator of the erbB2-, erbB3- and erbB4-(erbB-2/3/4) signaling pathway. Transfection of full-length
HRG cDNA into the
estrogen (E2)-dependent cell line MCF-7 promoted an invasive E2-independent phenotype, as well as persistent activation of the erbB-2/3/4 receptors. Moreover,
HRG expression in MCF-7 cells renders the cells sensitive to the
topoisomerase II inhibitor doxorubicin (Doxo). In an attempt to dissociate the tumorigenic effect of
HRG from the sensitizing effect to
chemotherapy, we constructed a structural deletion mutant of
HRG. Transfection of the deletion mutant of
HRG described in this study (
HRG/M) into MCF-7 cells resulted in the dissociation of the
tumor-promoting activity of
HRG from the sensitization to Doxo, that is, although the cells did not become more aggressive or E2-independent they became more sensitive to Doxo.
HRG/M was unable to autophosphorylate the
erbB receptors and did not affect the level of MAPK phosphorylation. Furthermore, the intracellular localization of the
protein was different from that of the full-length
protein. Our data show that the
HRG/M sequences are sufficient to sensitize MCF-7 cells to Doxo, and provide evidence that this sensitization is independent of erbB2 activation.