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 language | English |
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Pages (from-to) | 412-423.e9 |
Number of pages | 22 |
Journal | Cancer Cell |
Volume | 38 |
Issue number | 3 |
Early online date | 16 Jul 2020 |
DOIs | |
Publication status | Published - 14 Sept 2020 |
Keywords
- breast cancer
- estrogen receptor
- FOXA1
- IL6
- metastasis
- mouse intraductal xenograft model
- pioneer factor
- STAT3