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Comparison of matched primary and metastasis 4T1.2 syngeneic mammary tumor model of spontaneous bone metastasis

ABSTRACT: Breast cancer metastasis to bone is a critical determinant of long-term survival after treatment of primary tumors. We used a mouse model of spontaneous bone metastasis to determine new molecular mechanisms. Differential transcriptome comparisons of primary and metastatic tumor cells revealed that a substantial set of genes suppressed in bone metastases were highly enriched for promoter elements for the type I interferon (IFN) regulatory factor, Irf7, itself suppressed in mouse and human metastases. The critical function of the Irf7 pathway was demonstrated by restoration of exogenous Irf7 or systemic interferon administration, which significantly reduced bone metastases and prolonged metastasis-free survival. Using mice deficient in the type I receptor (Ifnar1-/-) or mature B, T and NK cell responses (NOD Scid IL-2rγ-/- mice), we demonstrated that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. Metastasis suppression correlated with decreased accumulation of myeloid-derived suppressor cells and increased CD4++, CD8 T cells and NK cells in the peripheral blood and was reversed by depletion of CD8+ cells and NK cells. Clinical importance of our findings was demonstrated as increased primary tumor Irf7 expression predicted prolonged bone and lung metastasis-free survival. Thus we report for the first time, a novel innate immune pathway, intrinsic to breast cancer cells, whose suppression in turn restricts systemic immunosurveillance to enable metastasis. This pathway may constitute a novel therapeutic target for restricting breast cancer metastases. Microarrays were used to profile transcriptional alterations inherent in tumor cells growing in bone when compared to matched primary tumor cells in the 4T1.2 murine mammary tumor model. Primary and metastasized tumor were isolated from the same mouse with 4 independent biological replicates.

ORGANISM(S): Mus musculus  

SUBMITTER: Brad Bidwell   Sam Forster  Paul Hertzog  Belinda Parker 

PROVIDER: E-GEOD-37975 | ArrayExpress | 2012-07-17



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