Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape

Bradley N. Bidwell, Clare Y. Slaney, Nimali P. Withana, Sam Forster, Yuan Cao, Sherene Loi, Daniel Andrews, Thomas Mikeska, Niamh E. Mangan, Shamith A. Samarajiwa, Nicole A. De Weerd, Jodee Gould, Pedram Argani, Andreas Müller, Mark J. Smyth, Robin L. Anderson, Paul J. Hertzog, Belinda S. Parker

Research output: Contribution to journalArticlepeer-review

273 Scopus citations


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 metastasisg-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.

Original languageEnglish (US)
Pages (from-to)1224-1231
Number of pages8
JournalNature medicine
Issue number8
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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