Inhibition of the autocrine IL-6–JAK2–STAT3–calprotectin axis as targeted therapy for HR−/HER2+ breast cancers
- Ruth Rodriguez-Barrueco1,8,
- Jiyang Yu2,3,8,
- Laura P. Saucedo-Cuevas1,
- Mireia Olivan1,
- David Llobet-Navas1,
- Preeti Putcha4,
- Veronica Castro4,
- Eva M. Murga-Penas4,
- Ana Collazo-Lorduy1,
- Mireia Castillo-Martin1,
- Mariano Alvarez2,3,
- Carlos Cordon-Cardo1,
- Kevin Kalinsky5,
- Matthew Maurer4,5,
- Andrea Califano2,3,6,7 and
- Jose M. Silva1
- 1Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 2Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA;
- 3Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA;
- 4Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA;
- 5Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;
- 6Department of Biomedical Informatics, Institute for Cancer Genetics, Columbia University, New York, New York 10032;
- 7Department of Biochemistry and Molecular Biophysics, Institute for Cancer Genetics, Columbia University, New York, New York 10032
- Corresponding authors: jose.silva{at}mssm.edu, califano{at}c2b2.columbia.edu
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↵8 These authors contributed equally to this work.
Abstract
HER2-positive (HER2+) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR−/HER2+ tumors, eliciting tumor dependency in these cells. Mechanistically, HR−/HER2+ cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6–Janus kinase 2 (JAK2)–STAT3–calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR−/HER2+ breast cancers, opening novel targeted therapeutic opportunities.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.262642.115.
- Received March 24, 2015.
- Accepted July 14, 2015.
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