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Genes Dev. 2015 Aug 1;29(15):1631-48. doi: 10.1101/gad.262642.115. Epub 2015 Jul 30.

Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.

Author information

1
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
2
Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA;
3
Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA;
4
Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;
5
Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA; Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;
6
Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA; Department of Biomedical Informatics, Institute for Cancer Genetics, Columbia University, New York, New York 10032; Department of Biochemistry and Molecular Biophysics, Institute for Cancer Genetics, Columbia University, New York, New York 10032.

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.

KEYWORDS:

HER2; STAT3; breast cancer; genetic screen; tailored therapies

PMID:
26227964
PMCID:
PMC4536311
DOI:
10.1101/gad.262642.115
[Indexed for MEDLINE]
Free PMC Article

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