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.
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This work was supported by the Cancer Council Victoria (B.S.P.), the Australian National Health and Medical Research Council (NHMRC) (P.J.H.), the Association of International Cancer Research (AICR) (A.M.), the Operational Infrastructure Scheme of the Victorian State government Department of Business and Innovation, the Australian Research Council (ARC) Centre for Structural and Functional Microbial Genomics and fellowship support for B.S.P. (NHMRC), R.L.A. (Australian National Breast Cancer Foundation, NBCF), A.M. (NBCF), C.Y.S. (NBCF, Cure Cancer Australia). We thank P. Hill (St Vincent's Pathology, St Vincent's Hospital, Fitzroy, Australia) for providing archived human breast cancer tissues assistance in the pathological assessment of immunohistochemistry staining and B. Haibe-Kains for assistance with codes in R. We also thank F. Miller (Karmanos Cancer Institute, Detroit, MI) for providing 66cl4 and 4T1 cell lines.
The authors declare no competing financial interests.
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Bidwell, B., Slaney, C., Withana, N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med 18, 1224–1231 (2012) doi:10.1038/nm.2830
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