title: ADAM-17: a novel therapeutic target for triple negative breast cancer.
abstract: BACKGROUND
  Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors.
  
  
  METHODS
  Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs.
  
  
  RESULTS
  In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents.
  
  
  CONCLUSIONS
  It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
authors.forename: P M
authors.initials: PM
authors.lastname: McGowan
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
authors.forename: M
authors.initials: M
authors.lastname: Mullooly
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
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; Department of Medical Oncology, St Vincent's University Hospital, Dublin.
authors.forename: S
authors.initials: S
authors.lastname: Sukor
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: S F
authors.initials: SF
authors.lastname: Madden
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
authors.forename: A A
authors.initials: AA
authors.lastname: Maguire
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
authors.forename: A
authors.initials: A
authors.lastname: Pierce
authors.affiliation: UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
authors.forename: E W
authors.initials: EW
authors.lastname: McDermott
authors.affiliation: Department of Medical Oncology, St Vincent's University Hospital, Dublin.
authors.forename: J
authors.initials: J
authors.lastname: Crown
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: O'Donovan
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin. Electronic address: patricia.mcgowan@ucd.ie.
authors.forename: M J
authors.initials: MJ
authors.lastname: Duffy
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D000072198:ADAM17 Protein; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066246:ErbB Receptors; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; C000606462:ADAM17 protein, human