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

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

doi:10.1016/j.ccell.2020.06.007

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

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

Authors

Rasmus Siersbaek

Valentina Scabia

Sankari Nagarajan

Igor Chernukhin

Evangelia K Papachristou

Rebecca Broome

Simon J Johnston

Stacey E P Joosten

ANDREW GREEN ANDREW.GREEN@NOTTINGHAM.AC.UK
Associate Professor

Sanjeev Kumar

Julia Jones

Soleilmane Omarjee

Ruben Alvarez-Fernandez

Silvia Glont

Sarah J Aitken

Kamal Kishore

Danya Cheeseman

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Clive D Santos

Wilbert Zwart

Alasdair Russell

Cathrin Brisken

Jason S Carroll

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.

Citation

Siersbaek, R., Scabia, V., Nagarajan, S., Chernukhin, I., Papachristou, E. K., Broome, R., …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

Journal Article Type	Article
Acceptance Date	Jun 12, 2020
Online Publication Date	Jul 16, 2020
Publication Date	Sep 14, 2020
Deposit Date	Jun 15, 2020
Publicly Available Date	Jul 17, 2021
Journal	Cancer Cell
Print ISSN	1535-6108
Electronic ISSN	1878-3686
Publisher	Cell Press
Peer Reviewed	Peer Reviewed
Volume	38
Issue	3
Pages	412-423.e9
DOI	https://doi.org/10.1016/j.ccell.2020.06.007
Keywords	estrogen receptorSTAT3IL6breast cancermetastasisFOXA1mouse intraductal xenograft modelpioneer factor
Public URL	https://nottingham-repository.worktribe.com/output/4655119
Publisher URL	https://www.sciencedirect.com/science/article/pii/S1535610820303111