肥胖是乳腺癌形成的公认风险因素，与升高的死亡率和不良预后有关。肥胖介导的炎症微环境有利于肿瘤的恶性进展。但是，详细的分子机制仍需进一步明确。我们发现，饮食诱导肥胖的小鼠乳腺癌细胞展示出增加的生长、侵袭和干性能力。转录组分析揭示，肥胖相关乳腺癌细胞中白细胞介素33 (IL33) 信号通路相关基因的表达升高。重要的是，IL33表达与是/否相关蛋白 (YAP) 签名显著相关，且IL33受YAP转录调控。抑制IL33可减少肿瘤的迁移和侵袭，而加入IL33则激活核因子 (NF)-κB信号通路并恢复在YAP沉默细胞中的肿瘤活动性。此外，抑制YAP可减弱伴随肥胖的免疫抑制并伴随着IL33表达的减弱。临床分析表明，IL33表达与巨噬细胞和调节性T细胞浸润明显相关。这些发现揭示了YAP/IL33轴在促进肥胖相关乳腺癌恶性进展和免疫抑制中的关键作用。 © 2023 Wiley Periodicals LLC.

Obesity is a well-known risk factor for breast cancer formation and is associated with elevated mortality and a poor prognosis. An obesity-mediated inflammatory microenvironment is conducive to the malignant progression of tumors. However, the detailed molecular mechanism is still needed to be clarified. Herein, we identified that breast cancer cells from mice with diet-induced obesity exhibited increased growth, invasiveness, and stemness capacities. A transcriptome analysis revealed that expressions of interleukin 33 (IL33) signaling pathway-related genes were elevated in obesity-associated breast cancer cells. Importantly, IL33 expression was significantly associated with the yes-associated protein (YAP) signature, and IL33 was transcriptionally regulated by YAP. Suppression of IL33 reduced tumor migration and invasion, while the addition of IL33 activated nuclear factor (NF)-κB signaling and revived tumor mobility in YAP-silenced cells. Furthermore, suppression of YAP attenuated IL33 expression which was accompanied by relief of obesity-mediated immunosuppression. Clinical analyses showed that IL33 expression was markedly associated with macrophage and regulatory T cell infiltration. These findings reveal a crucial role of the YAP/IL33 axis in promoting aggressiveness and immunosuppression of obesity-associated breast cancer progression.© 2023 Wiley Periodicals LLC.