title: TACE-dependent TGFα shedding drives triple-negative breast cancer cell invasion.
abstract: 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.
authors.affiliation: Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Orsi
authors.initials: O
authors.lastname: Giricz
authors.forename: Veronica
authors.initials: V
authors.lastname: Calvo
authors.forename: Esther A
authors.initials: EA
authors.lastname: Peterson
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Abouzeid
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms; D010766:Phosphorylation; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: TACE/ADAM17; epidermal growth factor receptor; transforming growth factor alpha; triple-negative breast cancer