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

Bradley Bidwell, Clare Y Slaney, Nimali P Withana, Samuel Forster, Yuan Cao, Sherene Loi, Daniel M Andrews, Thomas Mikeska, Niamh Mangan, Shamith A Samarajiwa, Nicole Anne De Weerd, Jodee Ann Gould, Pedram Argani, Andreas Muller, Mark Smyth, Robin Anderson, Paul John Hertzog, Belinda Parker

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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.
Original languageEnglish
Pages (from-to)1224 - 1231
Number of pages8
JournalNature Medicine
Volume18
Issue number8
DOIs
Publication statusPublished - 2012

Cite this

Bidwell, B., Slaney, C. Y., Withana, N. P., Forster, S., Cao, Y., Loi, S., ... Parker, B. (2012). Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nature Medicine, 18(8), 1224 - 1231. https://doi.org/10.1038/nm.2830
Bidwell, Bradley ; Slaney, Clare Y ; Withana, Nimali P ; Forster, Samuel ; Cao, Yuan ; Loi, Sherene ; Andrews, Daniel M ; Mikeska, Thomas ; Mangan, Niamh ; Samarajiwa, Shamith A ; De Weerd, Nicole Anne ; Gould, Jodee Ann ; Argani, Pedram ; Muller, Andreas ; Smyth, Mark ; Anderson, Robin ; Hertzog, Paul John ; Parker, Belinda. / Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. In: Nature Medicine. 2012 ; Vol. 18, No. 8. pp. 1224 - 1231.
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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.",
author = "Bradley Bidwell and Slaney, {Clare Y} and Withana, {Nimali P} and Samuel Forster and Yuan Cao and Sherene Loi and Andrews, {Daniel M} and Thomas Mikeska and Niamh Mangan and Samarajiwa, {Shamith A} and {De Weerd}, {Nicole Anne} and Gould, {Jodee Ann} and Pedram Argani and Andreas Muller and Mark Smyth and Robin Anderson and Hertzog, {Paul John} and Belinda Parker",
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Bidwell, B, Slaney, CY, Withana, NP, Forster, S, Cao, Y, Loi, S, Andrews, DM, Mikeska, T, Mangan, N, Samarajiwa, SA, De Weerd, NA, Gould, JA, Argani, P, Muller, A, Smyth, M, Anderson, R, Hertzog, PJ & Parker, B 2012, 'Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape', Nature Medicine, vol. 18, no. 8, pp. 1224 - 1231. https://doi.org/10.1038/nm.2830

Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. / Bidwell, Bradley; Slaney, Clare Y; Withana, Nimali P; Forster, Samuel; Cao, Yuan; Loi, Sherene; Andrews, Daniel M; Mikeska, Thomas; Mangan, Niamh; Samarajiwa, Shamith A; De Weerd, Nicole Anne; Gould, Jodee Ann; Argani, Pedram; Muller, Andreas; Smyth, Mark; Anderson, Robin; Hertzog, Paul John; Parker, Belinda.

In: Nature Medicine, Vol. 18, No. 8, 2012, p. 1224 - 1231.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape

AU - Bidwell, Bradley

AU - Slaney, Clare Y

AU - Withana, Nimali P

AU - Forster, Samuel

AU - Cao, Yuan

AU - Loi, Sherene

AU - Andrews, Daniel M

AU - Mikeska, Thomas

AU - Mangan, Niamh

AU - Samarajiwa, Shamith A

AU - De Weerd, Nicole Anne

AU - Gould, Jodee Ann

AU - Argani, Pedram

AU - Muller, Andreas

AU - Smyth, Mark

AU - Anderson, Robin

AU - Hertzog, Paul John

AU - Parker, Belinda

PY - 2012

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AB - 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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