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

Rasmus Siersbæk; 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 Zwart; Alasdair Russell; Cathrin Brisken; Jason S Carroll

doi:10.1016/j.ccell.2020.06.007

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

Cancer Cell. 2020 Sep 14;38(3):412-423.e9. doi: 10.1016/j.ccell.2020.06.007. Epub 2020 Jul 16.

Authors

Rasmus Siersbæk¹, Valentina Scabia², Sankari Nagarajan³, Igor Chernukhin³, Evangelia K Papachristou³, Rebecca Broome³, Simon J Johnston⁴, Stacey E P Joosten⁵, Andrew R Green⁴, Sanjeev Kumar⁶, Julia Jones³, Soleilmane Omarjee³, Ruben Alvarez-Fernandez³, Silvia Glont³, Sarah J Aitken⁷, Kamal Kishore³, Danya Cheeseman³, Emad A Rakha⁴, Clive D'Santos³, Wilbert Zwart⁸, Alasdair Russell³, Cathrin Brisken², Jason S Carroll⁹

Affiliations

¹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. Electronic address: siersbaek@bmb.sdu.dk.
² ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
⁴ Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK.
⁵ Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
⁷ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
⁸ Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands; Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. Electronic address: jason.carroll@cruk.cam.ac.uk.

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: FOXA1; IL6; STAT3; breast cancer; estrogen receptor; metastasis; mouse intraductal xenograft model; pioneer factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Hormonal / pharmacology
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics*
Breast Neoplasms / pathology
Enhancer Elements, Genetic / genetics*
Estrogen Receptor alpha / genetics*
Estrogen Receptor alpha / metabolism
Female
Fulvestrant / pharmacology
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Humans
Interleukin-6 / genetics*
Interleukin-6 / metabolism
Kaplan-Meier Estimate
MCF-7 Cells
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplasm Metastasis
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / metabolism
Signal Transduction / genetics*
Xenograft Model Antitumor Assays / methods

Substances

Antineoplastic Agents, Hormonal
Estrogen Receptor alpha
Interleukin-6
STAT3 Transcription Factor
Fulvestrant

Abstract

Publication types

MeSH terms

Substances

Grants and funding