TACE‐dependent TGFα shedding drives triple‐negative breast cancer cell invasion. Issue 11 (21st June 2013)

• Record Type: Journal Article
• Authors: Giricz, Orsi; Calvo, Veronica; Peterson, Esther A.; Abouzeid, Christiane M.; Kenny, Paraic A.
• Is Part Of: International journal of cancer. Volume 133:Issue 11(2013:Dec. 01)
• Page Start: 2587
• Page End: 2595
• Publication Date: 2013-06-21
• Subjects: triple‐negative breast cancer -- epidermal growth factor receptor -- TACE/ADAM17 -- transforming growth factor alpha; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28295
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? While expression of the Epidermal Growth Factor Receptor (EGFR) has been frequently associated with basal‐like and triple‐negative breast cancer, the mechanism by which it is activated remains unclear. In this study, Giricz and colleagues implicate TGF‐alpha as the most strongly up‐regulated ligand for the EGFR receptor in such tumors and demonstrate that TACE‐dependent proteolytic shedding of TGF‐alpha makes an important contribution to the invasion and growth of triple‐negative breast cancer cell lines. The data suggest that blocking TGF‐alpha/EGFR signaling using inhibitors of either TACE or EGFR may have clinical utility in patients whose tumors are dependent on this autocrine loop.