Transforming growth factor-alpha (TGF-alpha), like epidermal growth factor (EGF) and amphiregulin (AREG) binds exclusively to EGF receptor (EGFR). We have previously demonstrated that EGF, AREG and TGF-alpha down-regulate E-cadherin and induce ovarian cancer cell invasion, though whether these ligands use the same molecular mediators remains unknown. We now show that, like EGF, TGF-alpha- and AREG-induced E-cadherin down-regulation involves both EGFR and HER2. However, in contrast to EGF and AREG, the transcription factor Snail is not required for TGF-alpha-induced E-cadherin down-regulation. This study shows that TGF-alpha uses common and divergent molecular mediators to regulate E-cadherin expression and cell invasion. (C) 2015 Elsevier Inc. All rights reserved.