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

Luciano Castiello, Paola Sestili, Giovanna Schiavoni, Rosanna Dattilo, Domenica M. Monque, Fiorella Ciaffoni, Manuela Iezzi, Alessia Lamolinara, Antonella Sistigu, Federica Moschella, Anna Maria Pacca, Daniele Macchia, Maria Ferrantini, Ann Zeuner, Mauro Biffoni, Enrico Proietti, Filippo Belardelli, Eleonora Aricò

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)658-670
Number of pages13
JournalCancer immunology research
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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