Disruption of IFN I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells
Type I interferon (IFN I) inhibits tumor growth and activates antitumor responses. HER2 driven tumors in mice lacking IFN I receptor were more aggressive, more vascularized, and were enriched in stem cells, suggesting that IFN I exerts key control over tumor progression. 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 neu+ mice (neuT mice) IFNAR1 neu+ mice (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 neuT+ mammospheres and cell lines to antibodies to IFN I resulted in increased frequency of ALDH+ cells, 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. (c)2018 AACR.
Cancer Immunology Research