IL6/STAT3 signaling hijacks estrogen receptor α enhancers to drive breast cancer metastasis

Institution: Cancer Research UK Cambridge Institute, University of Cambridge

Corresponding Researcher: Jason Carroll

Email: jason.carroll@cruk.cam.ac.uk

Publication Link(s): https://doi.org/10.1016/j.ccell.2020.06.007

Data Link(s): http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126006 https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD012980

Keyword(s): FOXA1, IL6, STAT3, estrogen receptor, metastasis, mouse intraductal xenograft model, pioneer factor

Summary

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.