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PMID: 22820642 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature medicine ·Vol. 18 ·No. 8 ·2012-08-00 ·Pages 1224-31

Bidwell BN, Slaney CY, Withana NP, Forster S, Cao Y, Loi S, Andrews D, Mikeska T, Mangan NE, Samarajiwa SA, de Weerd NA, Gould J, Argani P, Möller A, Smyth MJ, Anderson RL, Hertzog PJ, Parker BS

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.

MeSH Terms
Animals Breast Neoplasms/genetics,immunology CD8-Positive T-Lymphocytes/immunology Female Gene Expression Profiling Gene Expression Regulation, Neoplastic/drug effects Gene Silencing Humans Immunologic Surveillance Interferon Regulatory Factor-7/antagonists & inhibitors,biosynthesis,genetics,physiology Interferon-Stimulated Gene Factor 3, gamma Subunit/antagonists & inhibitors,genetics,physiology Interferon-alpha/pharmacology Killer Cells, Natural/immunology Mammary Neoplasms, Experimental/genetics,immunology Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, SCID Neoplasm Metastasis/physiopathology Neoplasm Proteins/antagonists & inhibitors,genetics,physiology Receptors, Interferon/deficiency,physiology Recombinant Proteins/metabolism Severe Combined Immunodeficiency/genetics,immunology T-Lymphocyte Subsets/immunology Tumor Escape/genetics,physiology
Chemicals
IRF7 protein, human Interferon Regulatory Factor-7 Interferon-Stimulated Gene Factor 3, gamma Subunit Interferon-alpha Irf7 protein, mouse Isgf3g protein, mouse Neoplasm Proteins Receptors, Interferon Recombinant Proteins
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Bidwell Bradley N
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
Slaney Clare Y
Withana Nimali P
Forster Sam
Cao Yuan
Loi Sherene
Andrews Daniel
Mikeska Thomas
Mangan Niamh E
Samarajiwa Shamith A
de Weerd Nicole A
Gould Jodee
Argani Pedram
Möller Andreas
Smyth Mark J
Anderson Robin L
Hertzog Paul J
Parker Belinda S
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2830
Published
2012-08-00
Epub
2012-00-22
Pages
1224-31
Language
English
Region
United States
NLM ID
9502015
Subset
IM
Grants
Worldwide Cancer Research · 09-0676 · United Kingdom
External Links
PubMed source DOI: 10.1038/nm.2830 View journal details
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