title: Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance.
abstract: OBJECTIVE
  Only few predictive factors for the clinical activity of anti-epidermal growth factor receptor (EGFR) therapy are available. Mammary-derived growth inhibitor (MDGI) is a small cytosolic protein suggested to play a role in the differentiation of epithelial cells. Here, we have investigated the effect of MDGI expression on the EGFR signaling and cetuximab responsiveness of cancer cells.
  
  
  METHODS
  MDGI mRNA expression was investigated in clinical breast and lung cancer samples and in nontransformed and malignant cell lines. The effect of ectopic expression of MDGI on EGFR, ErbB2, and integrin function and traffic was investigated in breast and lung cancer cell lines using multiple methods. The effect of anti-EGFR agents on these cells were tested by cell proliferation measurements and by assessing tumor growth of breast cancer cells in cetuximab treated and control athymic nude mice.
  
  
  RESULTS
  Here, we show that although MDGI is absent in cultured cell lines because of epigenetic silencing, MDGI mRNA is expressed in 40% of clinical breast carcinomas and 85% of lung cancers. Ectopic expression of MDGI rendered breast and lung cancer cells resistant to the anti-EGFR antibody cetuximab in vitro and in an orthotopic breast cancer xenograft model in vivo. When expressed in cancer cells, MDGI induces intracellular accumulation of EGFR, but not ErbB2, and the internalized receptor is phosphorylated and not degraded.
  
  
  CONCLUSIONS
  MDGI-driven inherent desensitization of cancer cells is a novel molecular mechanism for resistance to the anti-EGFR antibody therapy, and MDGI may be a biomarker for responsiveness to anti-EGFR antibody therapy.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland.
authors.forename: Jonna
authors.initials: J
authors.lastname: Nevo
authors.forename: Elina
authors.initials: E
authors.lastname: Mattila
authors.forename: Teijo
authors.initials: T
authors.lastname: Pellinen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Yamamoto
authors.forename: Henri
authors.initials: H
authors.lastname: Sara
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D000068818:Cetuximab