The Epidermal Growth Factor Receptor is frequently expressed in triple-negative breast cancer and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, TGFalpha was expressed more highly in triple-negative breast tumors than in tumors of other subtypes. TGFalpha is synthesized as a transmembrane precursor requiring TACE/ADAM17-dependent proteolytic release in order to activate its receptor. In this study we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several triple-negative breast cancer cell lines. Each of the effects of the drug was reversed upon expression of a soluble TGFalpha mutant which does not require TACE activity, implicating this growth factor as a key metalloproteinase substrate for these phenotypes. Together, these data demonstrate that TACE-dependent TGFalpha shedding is a key process driving EGFR activation and subsequent proliferation and invasion in triple-negative breast cancer cell lines. © 2013 Wiley Periodicals, Inc.