IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis

Rasmus Siersbæk (Corresponding author), Valentina Scabia, Sankari Nagarajan, Igor Chernukhin, Evangelia K. Papachristou, Rebecca Broome, Simon J. Johnston, Stacey E.P. Joosten, Andrew R. Green, Sanjeev Kumar, Julia Jones, Soleilmane Omarjee, Ruben Alvarez-Fernandez, Silvia Glont, Sarah J. Aitken, Kamal Kishore, Danya Cheeseman, Emad A. Rakha, Clive D'Santos, Wilbert ZwartAlasdair Russell, Cathrin Brisken, Jason S. Carroll (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

131 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)412-423.e9
Number of pages22
JournalCancer Cell
Volume38
Issue number3
Early online date16 Jul 2020
DOIs
Publication statusPublished - 14 Sept 2020

Funding

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’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 ).

FundersFunder number
CSO of Azeria Therapeutics
KWF Dutch Cancer Society016.156.401, NKI 2014-6711, NKI 2015-7733
Alpe d'HuZes Bas Mulder Award
Wellcome Trust108467/Z/15/Z
Horizon 2020 Framework Programme859860, 646876
Cancer Research UK
University of Cambridge
European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Krebsliga SchweizSNF310030_179163, KFS-3701-08-2015
Novo Nordisk FondenNNF15OC0014136
Hutchison Whampoa Limited

    Keywords

    • breast cancer
    • estrogen receptor
    • FOXA1
    • IL6
    • metastasis
    • mouse intraductal xenograft model
    • pioneer factor
    • STAT3

    Fingerprint

    Dive into the research topics of 'IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis'. Together they form a unique fingerprint.

    Cite this