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:: R Siersbæk, V Scabia, S Nagarajan, I Chernukhin, EK Papachristou, R Broome, SJ Johnston, SEP Joosten, AR Green, S Kumar, J Jones, S Omarjee, R Alvarez-Fernandez, S Glont, SJ Aitken, K Kishore, D Cheeseman, EA Rakha, C D'Santos, W Zwart, A Russell, C Brisken, JS Carroll

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