Sun Yuwei, Fang Weilun, Peng Jinwu, Liu Xingling, Wang Chunjiang, Song Liying, Deng Zhenzhen
Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Eur J Med Res. 2025 Apr 10;30(1):265. doi: 10.1186/s40001-025-02532-4.
Breast cancer (BRCA), the most common malignancy among women, is a highly heterogeneous disease. Chemoresistance is a major factor leading to treatment failure in BRCA. However, mechanisms underlying the development of chemoresistance remain unclear.
In this study, we performed a comprehensive bioinformatic analysis to examine the role of cell death-associated genes in BRCA treatment. Specifically, we focused on caspase 8 and Fas-associated protein with death domain-like apoptosis regulator (CFLAR), which was identified as a co-differentially expressed cell death-associated molecule with potential prognostic values. We then validated these findings through in vitro experiments in BT- 549 and MDA-MB- 231 breast cancer cells.
Based on bioinformatics analysis, CFLAR expression was found to be downregulated in patients with BRCA, whereas its high expression was significantly associated with improved prognosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed CFLAR was potentially associated with oxidative phosphorylation, T cell receptor signaling, and NADH dehydrogenase (ubiquinone) activity. In vitro experiments demonstrated that overexpression of CFLAR inhibited the generation of reactive oxygen species (ROS), consequently promoting 5-fluorouracil (5-FU) sensitivity in BT- 549 and MDA-MB- 231 breast cancer cells. The expression of CFLAR was positively correlated with the abundance of several tumor-infiltrating immune cells, especially CD8 + T cells, further supporting the role of CFLAR in immune regulation.
In conclusion, this study reveals the novel roles of CFLAR in enhancing chemotherapy sensitivity and patient outcome in BRCA and underscores its potential as a therapeutic target. These results supported CFLAR as a therapeutic target and prognostic biomarker in BRCA patients.
乳腺癌（BRCA）是女性中最常见的恶性肿瘤，是一种高度异质性疾病。化疗耐药是导致BRCA治疗失败的主要因素。然而，化疗耐药发生发展的机制仍不清楚。
在本研究中，我们进行了全面的生物信息学分析，以研究细胞死亡相关基因在BRCA治疗中的作用。具体而言，我们聚焦于半胱天冬酶8和含死亡结构域样凋亡调节因子的Fas相关蛋白（CFLAR），其被鉴定为具有潜在预后价值的共差异表达细胞死亡相关分子。然后，我们通过对BT-549和MDA-MB-231乳腺癌细胞进行体外实验来验证这些发现。
基于生物信息学分析，发现BRCA患者中CFLAR表达下调，而其高表达与预后改善显著相关。京都基因与基因组百科全书（KEGG）通路分析表明，异常表达的CFLAR可能与氧化磷酸化、T细胞受体信号传导和NADH脱氢酶（泛醌）活性有关。体外实验表明，CFLAR的过表达抑制了活性氧（ROS）的产生，从而提高了BT-549和MDA-MB-231乳腺癌细胞对5-氟尿嘧啶（5-FU）的敏感性。CFLAR的表达与几种肿瘤浸润免疫细胞的丰度呈正相关，尤其是CD8 + T细胞，进一步支持了CFLAR在免疫调节中的作用。
总之，本研究揭示了CFLAR在增强BRCA化疗敏感性和患者预后方面的新作用，并强调了其作为治疗靶点的潜力。这些结果支持CFLAR作为BRCA患者的治疗靶点和预后生物标志物。
