Growth factor systems (ligands and their receptors) are targets of ethanol toxicity. Inasmuch as alcohol consumption may increase the risk and development of breast cancer, we hypothesize that ethanol enhances cell migration by up-regulating the activities of erbB receptors. Of the three tested breast cancer cell lines that exhibit low invasion capacity (BT-20, MCF-7, and T47D cells), erbB receptors were specifically affected by ethanol only in the T47D cells. Ethanol increased erbB2, erbB3, and erbB4 expression in T47D human breast cancer cells in a concentration-dependent manner. ErbB1 (epidermal growth factor receptor) was unaffected. Heregulin beta 1 (ligand for erbB3 and erbB4) induced a modest increase in the invasion potential of the T47D cells. Ethanol alone also promoted modest invasion by the T47D cells, however, ethanol dramatically increased their heregulin-mediated invasion. Knocking-out erbB2 with an anti-sense oligonucleotide eliminated heregulin beta 1-promoted migration and blocked ethanol-induced chemo-migration. Thus, these data suggest that alcohol may enhance metastasis by altering an erbB system, and pivotally, erbB2.