title: MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib.
abstract: BACKGROUND
  Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC.
  
  
  METHODS
  We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays.
  
  
  RESULTS
  Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours.
  
  
  CONCLUSIONS
  We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Cassandre
authors.initials: C
authors.lastname: Yip
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.|Department of Medical Oncology, University Hospital of Liège (CHU), Liège 4000, Belgium.|Faculty of Medicine, University of Liège, Liège 4000, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Foidart
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège 4000, Belgium.
authors.forename: Joan
authors.initials: J
authors.lastname: Somja
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Alice
authors.initials: A
authors.lastname: Truong
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Lienard
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Feyereisen
authors.affiliation: Department of Medical Oncology, University Hospital of Liège (CHU), Liège 4000, Belgium.
authors.forename: Hélène
authors.initials: H
authors.lastname: Schroeder
authors.affiliation: Biobank (Biothèque Universitaire de Liège), University of Liège, Liège 4000, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gofflot
authors.affiliation: Department of Biostatistics, University of Liège, 4000 Liège, Belgium.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Donneau
authors.affiliation: Department of Medical Oncology, University Hospital of Liège (CHU), Liège 4000, Belgium.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Collignon
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège 4000, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.affiliation: Department of Medical Oncology, University Hospital of Liège (CHU), Liège 4000, Belgium.|Faculty of Medicine, University of Liège, Liège 4000, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015251:Epirubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D015251:Epirubicin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C402225:MMP17 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated