title: Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells.
abstract: BACKGROUND
  Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC.
  
  
  METHODS
  We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines.
  
  
  RESULTS
  D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells.
  
  
  CONCLUSIONS
  Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: Caiazza
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: P M
authors.initials: PM
authors.lastname: McGowan
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Mullooly
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Murray
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Synnott
authors.affiliation: National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: O'Donovan
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Flanagan
authors.affiliation: 1] Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK [2] Cell Communication Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Tape
authors.affiliation: Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.affiliation: Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Crown
authors.affiliation: 1] UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland [2] UCD Clinical Research Centre, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Duffy
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D000072198:ADAM17 Protein; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human