Background:Inflammatory breast cancer (IBC) is a rare subtype of breast cancer accounting for 7% of breast cancer-related fatalities. There is an urgent need to develop new targeted treatments for IBC. The progression of IBC has been associated with alterations in growth factor and cytokine signaling; however, the function of the LIF (leukemia inhibitory factor)/LIFR (leukemia inhibitory factor receptor) cytokine pathway in the progression of IBC remains unknown. This study evaluated the role of LIFR signaling and tested the efficacy of the LIFR inhibitor EC359 in treating IBC.Methods:The utility of using LIFR inhibition as a treatment strategy in IBC was tested using cell survival, apoptosis, colony formation, invasion, and pre-clinical KPL4 xenografts. Western blotting, siRNA, RT-qPCR, and lipid peroxidation assays were used to establish the mechanism of EC359 therapy.Results:The reduction in LIFR levels using siRNA markedly decreased growth in colony formation assays and reduced the invasion of IBC cells. Pharmacological inhibition of LIFR with EC359 effectively reduced cell survival and the clonogenic capacity of IBC cells. RT-qPCR assays revealed that EC359 markedly decreased the expression of the LIFR target genes. Western blot analyses confirmed that EC359 treatment suppressed downstream LIF/LIFR signaling pathways and promoted apoptosis. Treatment of cells with the ferroptosis inhibitor Fer-1 negated the capacity of EC359 to induce apoptosis. Mechanistic investigations demonstrated that EC359 predominantly triggered ferroptosis by inhibiting the glutathione antioxidant defense system through the downregulation of Glutathione peroxidase 4 (GPX4) levels. EC359 (5 mg/kg/day) was effective in reducing the growth of the IBC KPL4 xenograft tumors.Conclusion:These findings demonstrates that LIFR inhibition promote ferroptosis-mediated cell death in IBC and that EC359 represent novel therapeutic for IBC treatment.
背景：炎性乳腺癌是一种罕见的乳腺癌亚型，占乳腺癌相关死亡病例的7%。目前迫切需要开发针对炎性乳腺癌的新型靶向治疗方法。炎性乳腺癌的进展与生长因子和细胞因子信号通路的改变相关；然而，白血病抑制因子及其受体细胞因子通路在炎性乳腺癌进展中的作用尚不明确。本研究评估了白血病抑制因子受体信号通路的作用，并测试了其抑制剂EC359治疗炎性乳腺癌的疗效。 方法：通过细胞存活、凋亡、克隆形成、侵袭实验以及临床前KPL4异种移植模型，验证了抑制白血病抑制因子受体作为炎性乳腺癌治疗策略的可行性。采用蛋白质印迹、小干扰RNA、实时定量聚合酶链反应及脂质过氧化测定等方法，阐明了EC359的治疗机制。 结果：使用小干扰RNA降低白血病抑制因子受体水平，显著抑制了炎性乳腺癌细胞的克隆形成生长并降低了其侵袭能力。EC359对白血病抑制因子受体的药理学抑制有效降低了炎性乳腺癌细胞的存活率和克隆形成能力。实时定量聚合酶链反应检测显示，EC359显著降低了白血病抑制因子受体靶基因的表达。蛋白质印迹分析证实，EC359处理抑制了下游白血病抑制因子及其受体信号通路，并促进了细胞凋亡。使用铁死亡抑制剂Fer-1处理细胞可抵消EC359诱导凋亡的能力。机制研究表明，EC359主要通过下调谷胱甘肽过氧化物酶4水平抑制谷胱甘肽抗氧化防御系统，从而触发铁死亡。EC359（每日5毫克/千克）能有效抑制炎性乳腺癌KPL4异种移植瘤的生长。 结论：这些发现表明，抑制白血病抑制因子受体可促进炎性乳腺癌中铁死亡介导的细胞死亡，EC359代表了治疗炎性乳腺癌的新型疗法。
肿瘤(癌症)患者之家