Abstract
Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / immunology
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CD8-Positive T-Lymphocytes / immunology
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic* / drug effects
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Gene Silencing*
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Humans
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Immunologic Surveillance
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Interferon Regulatory Factor-7 / antagonists & inhibitors
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Interferon Regulatory Factor-7 / biosynthesis
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Interferon Regulatory Factor-7 / genetics
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Interferon Regulatory Factor-7 / physiology*
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Interferon-Stimulated Gene Factor 3, gamma Subunit / antagonists & inhibitors
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Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
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Interferon-Stimulated Gene Factor 3, gamma Subunit / physiology
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Interferon-alpha / pharmacology
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Killer Cells, Natural / immunology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Metastasis / physiopathology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Receptors, Interferon / deficiency
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Receptors, Interferon / physiology
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Recombinant Proteins / metabolism
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Severe Combined Immunodeficiency / genetics
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Severe Combined Immunodeficiency / immunology
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T-Lymphocyte Subsets / immunology
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Tumor Escape / genetics
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Tumor Escape / physiology*
Substances
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IRF7 protein, human
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Interferon Regulatory Factor-7
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interferon-alpha
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Irf7 protein, mouse
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Isgf3g protein, mouse
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Neoplasm Proteins
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Receptors, Interferon
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Recombinant Proteins