title: Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer.
abstract: BACKGROUND
  Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer.
  
  
  METHODS
  Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively.
  
  
  RESULTS
  The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells.
  
  
  CONCLUSIONS
  Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Marie-Emmanuelle
authors.initials: ME
authors.lastname: Legrier
authors.affiliation: Genetics Department, Hospital, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Gaston
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Beurdeley
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yvonnet
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Déas
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thuleau
authors.affiliation: Department of Pathology, Veterinary School of Alfort, Maisons-Alfort 94704, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Château-Joubert
authors.affiliation: Department of Pathology, Veterinary School of Alfort, Maisons-Alfort 94704, France.|INRA, Phase Department, Nouzilly, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Servely
authors.affiliation: Genetics Department, Hospital, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Lassalle
authors.affiliation: Institut de Recherches Servier, PIT Oncology, Croissy-sur-Seine 78290, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.affiliation: Institut de Recherches Servier, PIT Oncology, Croissy-sur-Seine 78290, France.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Tucker
authors.affiliation: Department of Pathology, Veterinary School of Alfort, Maisons-Alfort 94704, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fontaine
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Judde
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.|Medical Oncology Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: XenTech, 4 rue Pierre Fontaine, Evry 91000, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000941:Antigens / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000069287:Capecitabine / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016899:Interferon-beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D064547:Myxovirus Resistance Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014452:Ubiquitins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; C406887:IFI27 protein, human; C065888:IFI44 protein, human; C468762:IFI6 protein, human; C484290:IFIT1 protein, human; C116468:IFIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C579071:MX1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D064547:Myxovirus Resistance Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014452:Ubiquitins; C074034:ISG15 protein, human; D000069287:Capecitabine; D016899:Interferon-beta; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin