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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 38 Issue 3 Pg. 412-423.e9 (09 14 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 32679107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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