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 ZwartAlasdair Russell, Cathrin Brisken, Jason S Carroll

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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.

OriginalsprogEngelsk
TidsskriftCancer Cell
Vol/bind38
Udgave nummer3
Sider (fra-til)412-423.e9
ISSN1535-6108
DOI
StatusUdgivet - 14. sep. 2020
Udgivet eksterntJa

Bibliografisk note

Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

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