title: Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity.
abstract: BACKGROUND
  Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes on ADCC.
  
  
  METHODS
  We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in a mouse xenograft model.
  
  
  RESULTS
  We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or degradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killer cells, but did not alter natural killer cells' cytotoxicity. Preincubation of breast cancer cells with the conditioned medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium. Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.
  
  
  CONCLUSIONS
  Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. mn.duong@hotmail.com.
authors.forename: Minh Ngoc
authors.initials: MN
authors.lastname: Duong
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. aurore.cleret@univ-lyon1.fr.
authors.forename: Aurore
authors.initials: A
authors.lastname: Cleret
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. eva-laure.matera@univ-lyon1.fr.
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. abdelkamel.chettab@univ-lyon1.fr.
authors.forename: Kamel
authors.initials: K
authors.lastname: Chettab
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. doriane.mathe@univ-lyon1.fr.
authors.forename: Doriane
authors.initials: D
authors.lastname: Mathé
authors.affiliation: Centre Léon Bérard, Pôle des sciences cliniques, Plateforme d'innovations en immunomonitoring et immunothérapie, 28 Promenade Léa et Napoléon Bullukian, 69008, Lyon, France. sandrine.wittmann@lyon.unicancer.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Valsesia-Wittmann
authors.affiliation: INSERM U892, Centre de Recherche en Cancérologie Nantes-Angers, 8 quai Moncousu, BP 70721, 44007, Nantes Cedex, France. beatrice.clemenceau@inserm.fr.|Centre Hospitalier Universitaire de Nantes, 1 Place Alexis-Ricordeau, 44000, Nantes, France. beatrice.clemenceau@inserm.fr.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Clémenceau
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France. charles.dumontet@chu-lyon.fr.|Hospices Civils de Lyon, 165 Chemin du Grand Revoyet, 69310, Pierre-Bénite, France. charles.dumontet@chu-lyon.fr.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D017077:Culture Media, Conditioned; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D051379:Mice; D000068878:Trastuzumab / Q000276:immunology* / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D017077:Culture Media, Conditioned; D000068878:Trastuzumab