@article{3a4e450c412840da81d5d7ddb456cb43,
title = "IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis",
abstract = "The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor α (ER) in breast cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER+ breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program. Although these enhancers are shared by both STAT3 and ER, IL6/STAT3 activity is refractory to standard ER-targeted therapies. Instead, inhibition of STAT3 activity using the JAK inhibitor ruxolitinib decreases breast cancer invasion in vivo. Therefore, IL6/STAT3 and ER oncogenic pathways are functionally decoupled, highlighting the potential of IL6/STAT3-targeted therapies in ER+ breast cancer.",
keywords = "Cancer, IL6, STAT3, Estrogen receptor, Breast cancer, enhancers",
author = "Sankari Nagarajan",
note = "Funding Information: We thank Carlos Caldas and Alejandra Bruna for providing PDX material for the explant experiments and Kelly Holmes for generating the parental luciferase-mStrawberry expressing MCF7 cells used for generating STAT3 −/− clones. We also thank the core facilities at Cancer Research UK (genomics, proteomics, histopathology, pre-clinical genome editing, bioinformatics, biorepository, flow cytometry, research instrumentation), in particular Cara Brodie from the histopathology core, for technical support. We thank the NKI Core Facility Molecular Pathology and Karianne Schuurman for technical support and Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We would like to acknowledge the support of the University of Cambridge , Cancer Research UK and Hutchison Whampoa Limited . J.S.C. is funded by Cancer Research UK , an ERC Consolidator Award, and a Komen Scholarship. R.S. is funded by the Novo Nordisk Foundation ( NNF15OC0014136 ). C.B. received funding from the Swiss Cancer Ligue KFS-3701-08-2015 and SNF310030_179163 . W.Z. is supported by a KWF Dutch Cancer Society /Alpe d{\textquoteright}HuZes Bas Mulder Award ( NKI 2014-6711 ), a KWF Dutch Cancer Society research grant ( NKI 2015-7733 ), and a VIDI grant ( 016.156.401 ) from The Netherlands Organisation for Scientific Research (NWO). The Fusion Lumos Orbitrap mass spectrometer was purchased with the support from a Wellcome Trust Multi-user Equipment grant (grant # 108467/Z/15/Z ). Publisher Copyright: {\textcopyright} 2020 Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = sep,
day = "14",
doi = "10.1016/j.ccell.2020.06.007",
language = "English",
volume = "38",
pages = "412--423.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}
