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

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)

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

177 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 language	English
Pages (from-to)	412-423.e9
Number of pages	22
Journal	Cancer Cell
Volume	38
Issue number	3
Early online date	16 Jul 2020
DOIs	https://doi.org/10.1016/j.ccell.2020.06.007
Publication status	Published - 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 ).

Funders	Funder number
KWF Dutch Cancer Society	016.156.401, NKI 2014-6711, NKI 2015-7733
Wellcome Trust	108467/Z/15/Z
European Union's Horizon 2020 - Research and Innovation Framework Programme	859860, 646876
Cancer Research UK Cambridge Institute
University of Cambridge
H2020 European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Novo Nordisk Fonden	NNF15OC0014136

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Siersbæk, R., Scabia, V., Nagarajan, S., Chernukhin, I., Papachristou, E. K., Broome, R., Johnston, S. J., Joosten, S. E. P., Green, A. R., Kumar, S., Jones, J., Omarjee, S., Alvarez-Fernandez, R., Glont, S., Aitken, S. J., Kishore, K., Cheeseman, D., Rakha, E. A., D'Santos, C., ... Carroll, J. S. (2020). IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis. Cancer Cell, 38(3), 412-423.e9. https://doi.org/10.1016/j.ccell.2020.06.007

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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 = "breast cancer, estrogen receptor, FOXA1, IL6, metastasis, mouse intraductal xenograft model, pioneer factor, STAT3",

author = "Rasmus Siersb{\ae}k and Valentina Scabia and Sankari Nagarajan and Igor Chernukhin and Papachristou, {Evangelia K.} and Rebecca Broome and Johnston, {Simon J.} and Joosten, {Stacey E.P.} and Green, {Andrew R.} and Sanjeev Kumar and Julia Jones and Soleilmane Omarjee and Ruben Alvarez-Fernandez and Silvia Glont and Aitken, {Sarah J.} and Kamal Kishore and Danya Cheeseman and Rakha, {Emad A.} and Clive D'Santos and Wilbert Zwart and Alasdair Russell and Cathrin Brisken and Carroll, {Jason S.}",

year = "2020",

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doi = "10.1016/j.ccell.2020.06.007",

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Siersbæk, R, Scabia, V, Nagarajan, S, Chernukhin, I, Papachristou, EK, Broome, R, Johnston, SJ, Joosten, SEP, Green, AR, Kumar, S, Jones, J, Omarjee, S, Alvarez-Fernandez, R, Glont, S, Aitken, SJ, Kishore, K, Cheeseman, D, Rakha, EA, D'Santos, C, Zwart, W, Russell, A, Brisken, C & Carroll, JS 2020, 'IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis', Cancer Cell, vol. 38, no. 3, pp. 412-423.e9. https://doi.org/10.1016/j.ccell.2020.06.007

TY - JOUR

T1 - IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis

AU - Siersbæk, Rasmus

AU - Scabia, Valentina

AU - Nagarajan, Sankari

AU - Chernukhin, Igor

AU - Papachristou, Evangelia K.

AU - Broome, Rebecca

AU - Johnston, Simon J.

AU - Joosten, Stacey E.P.

AU - Green, Andrew R.

AU - Kumar, Sanjeev

AU - Jones, Julia

AU - Omarjee, Soleilmane

AU - Alvarez-Fernandez, Ruben

AU - Glont, Silvia

AU - Aitken, Sarah J.

AU - Kishore, Kamal

AU - Cheeseman, Danya

AU - Rakha, Emad A.

AU - D'Santos, Clive

AU - Zwart, Wilbert

AU - Russell, Alasdair

AU - Brisken, Cathrin

AU - Carroll, Jason S.

PY - 2020/9/14

Y1 - 2020/9/14

N2 - 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.

AB - 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.

KW - breast cancer

KW - estrogen receptor

KW - FOXA1

KW - IL6

KW - metastasis

KW - mouse intraductal xenograft model

KW - pioneer factor

KW - STAT3

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U2 - 10.1016/j.ccell.2020.06.007

DO - 10.1016/j.ccell.2020.06.007

M3 - Article

C2 - 32679107

AN - SCOPUS:85089298903

SN - 1535-6108

VL - 38

SP - 412-423.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

Funding

Keywords

UN SDGs

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