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 构成了关键的致癌途径，该途径被认为与乳腺癌中的雌激素受体 α (ER) 功能相关。我们证明 IL6/STAT3 信号传导独立于 ER 驱动 ER ⁺乳腺癌转移。 STAT3 劫持 ER 增强子的子集来驱动独特的转录程序。尽管这些增强子是 STAT3 和 ER 共有的，但标准 ER 靶向疗法难以发挥 IL6/STAT3 活性。相反，使用 JAK 抑制剂鲁索替尼抑制 STAT3 活性可减少乳腺癌体内侵袭。因此，IL6/STAT3 和 ER 致癌途径在功能上是解耦的，凸显了 IL6/STAT3 靶向治疗在 ER ⁺乳腺癌中的潜力。