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.

细胞因子白细胞介素 6 (IL6) 及其下游效应子 STAT3 构成了一个关键的致癌途径，被认为在功能上与乳腺癌中的雌激素受体 α (ER) 相关。我们证明 IL6/STAT3 信号传导驱动 ER ⁺乳腺癌中的转移，独立于 ER。STAT3 劫持 ER 增强子的一个子集来驱动一个独特的转录程序。尽管这些增强剂由 STAT3 和 ER 共享，但 IL6/STAT3 活性对标准的 ER 靶向疗法是难以控制的。相反，使用 JAK 抑制剂鲁索替尼抑制 STAT3 活性可减少体内乳腺癌的侵袭。因此，IL6/STAT3 和 ER 致癌途径在功能上是解耦的，突出了 IL6/STAT3 靶向治疗在 ER ^{+中的潜力} 乳腺癌。