Disruption of IFN-I signaling promotes HER2/Neu tumor progression and breast cancer stem cells

L. Castiello, P. Sestili, G. Schiavoni, R. Dattilo, D.M. Monque, F. Ciaffoni, M. Iezzi, A. Lamolinara, A. Sistigu, F. Moschella, A.M. Pacca, D. Macchia, M. Ferrantini, A. Zeuner, M. Biffoni, E. Proietti, F. Belardelli, E. Aricò

Research output: Contribution to journalArticle

Abstract

Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neumice (neuT mice), IFNAR1/ neumice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuTmmospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDHlls, suggesting that IFN-I controls stemness in tumor cells.Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658-70. © 2018 AACR.
Original languageEnglish
Pages (from-to)658-670
Number of pages13
JournalCancer immunology research
Volume6
Issue number6
DOIs
Publication statusPublished - 2018

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Keywords

  • aldehyde dehydrogenase 1a1
  • aldehyde dehydrogenase isoenzyme 1
  • epidermal growth factor receptor 2
  • interferon
  • unclassified drug
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • breast cancer
  • cancer cell
  • cancer growth
  • cancer patient
  • cancer prognosis
  • cancer stem cell
  • clonogenic assay
  • comparative study
  • enzyme activity
  • female
  • human
  • immunocompetent cell
  • immunohistochemistry
  • immunomodulation
  • immunophenotyping
  • in vitro study
  • in vivo study
  • male
  • mouse
  • nonhuman
  • oncogene neu
  • promoter region
  • RNA hybridization
  • RNA isolation

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