American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.
患有肥胖症的美国女性三阴性乳腺癌（TNBC）发病率升高。肥胖状态对肿瘤微环境的影响被认为会加速TNBC进展，但其具体机制尚不明确。本研究探讨了肥胖上调TNBC中白血病抑制因子受体（LIFR）致癌信号传导的假说，并评估了EC359抑制LIFR在阻断TNBC进展中的疗效。将TNBC细胞系与人原代脂肪细胞或脂肪细胞条件培养基共培养，并用EC359处理。通过细胞活力、克隆形成和侵袭实验评估肥胖环境的影响。机制研究采用RNA测序、蛋白质印迹、实时定量PCR和报告基因检测。利用异种移植模型和患者来源类器官（PDO）模型测试EC359的治疗潜力。结果显示，脂肪环境可促进TNBC细胞增殖和侵袭，这些效应与LIFR信号增强相关。相应地，EC359处理在脂肪环境下降低了细胞活力、克隆形成和侵袭能力，并阻断了脂肪介导的类器官生长及TNBC异种移植瘤的生长。RNA测序分析揭示了饮食诱导肥胖小鼠模型中LIF/LIFR信号调控的关键通路。这些发现表明，肥胖通过激活LIF/LIFR通路促进TNBC进展，而使用EC359抑制LIFR为肥胖相关TNBC提供了潜在的治疗策略。
肿瘤(癌症)患者之家