Zhu Lei, Chen Mu, Huang Bingsong, Zhang Tao, Chen Kui, Lian Hao, Liu Min, Zhao Kaijun, Pang Ying, Zhang Jing, Li Qinchuan, Zhong Chunlong
Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Genet. 2022 Jan 25;12:819632. doi: 10.3389/fgene.2021.819632. eCollection 2021.
The role of ferroptosis in breast cancer brain metastasis (BCBM) is unclear. This study aimed to explore the ferroptosis-related genes (FRG) relations with the tumor microenvironment, as well as evaluate their values in predicting survival and drug sensitivity in patients with BCBM. Genes expression and clinical data were downloaded from Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses were performed to explore the independent prognostic factors. Consensus cluster principal component analysis (PCA) was used to establish the ferroptosis score. Immunological signatures were analyzed by the single-sample gene set enrichment analysis (ssGSEA). Drug sensitivity was evaluated through the estimated half-maximal inhibitory concentration (IC50). Finally, results were validated in external cohorts. Fourteen significantly different FRG were identified between breast cancer (BC) and BCBM tissues. Survival analysis demonstrated HMOX1, PEBP1, KEAP1, and LPCAT3 were significantly associated with overall survival (OS) and relapse-free survival (RFS) (all < 0.05). High ferroptosis score was correlated with iron ion homeostasis, iron metabolism, higher stromal cells and immune cells scores. Patients with high- and low-ferroptosis scores were characterized by different drug sensitivities. Following external validations, the ferroptosis had distinct expression profiles between the BC and BCBM, and could serve as biomarkers for OS and drug response. Our findings suggested that ferroptosis may be involved in the process of BCBM, and ferroptosis could serve as prognostic biomarkers. Evaluation of ferroptosis may deepen our understanding about the tumor microenvironment, and could help clinicians to make individualized therapy.
铁死亡在乳腺癌脑转移（BCBM）中的作用尚不清楚。本研究旨在探讨铁死亡相关基因（FRG）与肿瘤微环境的关系，并评估其在预测BCBM患者生存和药物敏感性方面的价值。基因表达和临床数据从基因表达综合数据库（GEO）下载。进行单因素和多因素Cox回归分析以探索独立预后因素。采用一致性聚类主成分分析（PCA）建立铁死亡评分。通过单样本基因集富集分析（ssGSEA）分析免疫特征。通过估计的半数最大抑制浓度（IC50）评估药物敏感性。最后，在外部队列中验证结果。在乳腺癌（BC）和BCBM组织之间鉴定出14个显著不同的FRG。生存分析表明，血红素加氧酶1（HMOX1）、磷脂酰乙醇胺结合蛋白1（PEBP1）、 Kelch样环氧氯丙烷相关蛋白1（KEAP1）和溶血磷脂酰胆碱酰基转移酶3（LPCAT3）与总生存期（OS）和无复发生存期（RFS）显著相关（均P<0.05）。高铁死亡评分与铁离子稳态、铁代谢、较高的基质细胞和免疫细胞评分相关。高铁死亡评分和低铁死亡评分的患者具有不同的药物敏感性。经过外部验证，铁死亡在BC和BCBM之间具有不同的表达谱，并且可以作为OS和药物反应的生物标志物。我们的研究结果表明，铁死亡可能参与BCBM的过程，并且铁死亡可以作为预后生物标志物。评估铁死亡可能会加深我们对肿瘤微环境的理解，并有助于临床医生制定个体化治疗方案。
