Department of Thyroid and Breast Surgery, Hubei General Hospital, Renmin Hospital of Wuhan University, Wuhan, 430000, China.
Department of Thyroid and Breast Surgery, Yichang Central People's Hospital, The First Clinical College of Three Gorges University, Yichang, 443000, China.
Sci Rep. 2024 Feb 27;14(1):4732. doi: 10.1038/s41598-024-55561-0.
Triple-negative breast cancer (TNBC) is currently the type of breast cancer with the worst prognosis; it lacks specific treatments, such as ER/PR antagonistic endocrine and anti-HER2 targeted therapies. Although immunotherapy with immune checkpoints has shown some efficacy in many solid tumors, clinical data in TNBC suggest significant limitations. The essence of ferroptosis is the impaired metabolism of intracellular lipid oxides, which in turn causes the activation and abnormalities of the immune system, including ROS, and not only plays an important role in liver injury and organ aging but also a large amount of data points to the close correlation between the ferroptosis process and tumor development. In this study, through the analysis of large-throughput biological data of breast tumors, combined with the characteristics of the biological process of ferroptosis, the specific gene IDH2 was found to be significantly highly expressed in TNBC and functionally correlated with ferroptosis. Through clinical specimens validated at the gene and protein levels, in vitro tumor cell line validation, and in vivo mouse models, we found that the high expression of IDH2 in TNBC has a role in inhibiting the ferroptosis process in TNBC, thus promoting the proliferation of TNBC cells and other malignant features.
三阴性乳腺癌（TNBC）是目前预后最差的乳腺癌类型；它缺乏特定的治疗方法，如 ER/PR 拮抗内分泌治疗和抗 HER2 靶向治疗。尽管免疫检查点免疫疗法在许多实体肿瘤中显示出一定的疗效，但 TNBC 的临床数据表明存在显著的局限性。铁死亡的本质是细胞内脂质氧化物代谢受损，进而导致免疫系统的激活和异常，包括 ROS，它不仅在肝损伤和器官老化中起着重要作用，而且大量数据表明铁死亡过程与肿瘤发展密切相关。在这项研究中，通过对乳腺癌大吞吐量生物数据的分析，结合铁死亡生物过程的特点，发现 IDH2 基因在 TNBC 中明显高表达，并且与铁死亡功能相关。通过基因和蛋白水平的临床标本验证、体外肿瘤细胞系验证和体内小鼠模型，我们发现 IDH2 在 TNBC 中的高表达在抑制 TNBC 中的铁死亡过程中起作用，从而促进 TNBC 细胞的增殖和其他恶性特征。
