The epidermal growth factor receptor (EGFR) is frequently expressed in 
triple-negative breast cancer (TNBC) 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, transforming growth factor alpha (TGFα) was expressed more highly in 
triple-negative breast tumors than in tumors of other subtypes. TGFα is 
synthesized as a transmembrane precursor requiring tumor necrosis factor alpha 
converting enzyme (TACE)/ADAM17-dependent proteolytic release to activate its 
receptor. In our study, we show that an inhibitor of this proteolytic release 
blocks invasion, migration and colony formation by several TNBC cell lines. Each 
of the effects of the drug was reversed upon expression of a soluble TGFα mutant 
that does not require TACE activity, implicating this growth factor as a key 
metalloproteinase substrate for these phenotypes. Together, these data 
demonstrate that TACE-dependent TGFα shedding is a key process driving EGFR 
activation and subsequent proliferation and invasion in TNBC cell lines.