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

Research output: Contribution to journalArticleAcademicpeer-review

8 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 languageEnglish
Pages (from-to)412-423.e9
Number of pages22
JournalCancer Cell
Volume38
Issue number3
Early online date16 Jul 2020
DOIs
Publication statusPublished - 14 Sep 2020

Keywords

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

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