Active cancer‐associated fibroblasts (CAFs), which constitute the most preponderant cell type in breast tumors, contribute actively to all aspects of cancer progression, stimulate recurrence, and restrain drug sensitivity. In the present study, we tested the effect of the selective JAK/STAT3 inhibitor cucurbitacin I (JSI‐124) on active breast CAFs. We have shown that JSI‐124 at non‐cytotoxic concentration (20 nM) can inhibit the IL‐6/STAT3/NF‐κB positive feedback loop in breast myofibroblasts, which enabled persistent inactivation of these cells. Interestingly, JSI‐124 treatment suppressed the paracrine promotion of the epithelial‐to‐mesenchymal transition (EMT) process and the pro‐migratory/‐invasive and ‐proliferative effects of CAFs on breast cancer cells in vitro. Similarly, JSI‐124 inhibited the capacity of CAF cells in promoting tumor growth, EMT, stemness as well as angiogenesis in orthotopic humanized breast cancer tumors. Together, these findings indicate that JSI‐124‐dependent inhibition of STAT3 could be of great therapeutic value for the treatment of breast cancer through targeting cancer cells as well as their growth supportive stromal fibroblasts and blood vessels. This could pave the path to developing a precise CAF‐targeted anticancer therapy.

中文翻译：

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葫芦素I（JSI-124）依赖性的STAT3抑制作用可永久抑制与乳腺癌相关的活跃成纤维细胞的促癌作用

活跃的癌症相关成纤维细胞（CAF）构成了乳腺肿瘤中最主要的细胞类型，可积极参与癌症进展的各个方面，刺激复发并抑制药物敏感性。在本研究中，我们测试了选择性JAK / STAT3抑制剂葫芦素I（JSI-124）对活动性乳腺癌CAF的作用。我们已经证明，非细胞毒性浓度（20 nM）的JSI-124可以抑制乳腺成纤维细胞中IL-6 / STAT3 /NF-κB阳性反馈环，从而使这些细胞持续失活。有趣的是，JSI-124治疗抑制了旁分泌促进上皮-间充质转化（EMT）过程，并抑制了CAFs在体外对乳腺癌细胞的迁移/侵袭和增殖作用。同样，JSI-124抑制CAF细胞促进肿瘤生长的能力，原位人源化乳腺癌肿瘤中的EMT，干细胞以及血管生成。总之，这些发现表明JSI-124依赖性的STAT3抑制通过靶向癌细胞及其生长支持性基质成纤维细胞和血管，对乳腺癌的治疗具有重要的治疗价值。这可能为开发精确的针对CAF的抗癌疗法铺平道路。