Hu Qingyi, Chen Qianzhi, Yang Wen, Ren Anwen, Tan Jie, Huang Tao
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Commun Signal. 2025 Jul 25;23(1):355. doi: 10.1186/s12964-025-02356-z.
Due to the lack of effective targeted therapies and the high likelihood of acquired resistance, triple-negative breast cancer (TNBC) remains one of the deadliest cancers affecting women globally. Investigating the mechanism underlying TNBC's resistance to platinum-based chemotherapy and identifying new therapeutic targets are urgent priorities.
The expression level of GPX3, cisplatin sensitivity, and ROS production were compared across three TNBC cell lines to elucidate the relationship between GPX3 and platinum resistance. RNA sequencing and bioinformatics analyses of GPX3 knockdown cells revealed its regulation of stress-related signaling pathways and TGFB1. The regulation of TGFB1 by GPX3 was further investigated using Western blotting, RNA interference, confocal microscopy, and inhibitor treatments. The correlation between the expression level of GPX3, TGFB1, and ZEB2 was analyzed using breast cancer microarrays and the TCGA database. The effect of GPX3 on platinum sensitivity in TNBC was studied using a mouse xenograft model.
GPX3 expression was upregulated in more invasive TNBC cells, promoting resistance to cisplatin-based chemotherapy. RNA sequencing revealed that the deletion of GPX3 resulted in a decrease in gene expression patterns associated with pro-tumor signaling pathways. Validation experiments confirmed that the upregulation of TGFB1 in acquired cisplatin resistance is highly dependent on GPX3. Further investigation revealed that the TGFB1-ZEB2 axis mediated platinum resistance and metastasis through epithelial-mesenchymal transition (EMT). Additionally, platinum treatment increased GPX3 and TGFB1 expression and secretion, and their depletion enhanced platinum sensitivity in TNBC cells. We identified the GPX3-TGFB1-ZEB2 regulatory axis and found a positive correlation in the expression of all three in clinical samples. Our study also demonstrated that GPX3 knockdown inhibited TNBC tumor growth in platinum-treated mouse models.
This study reveals the signaling pathway mediated by GPX3-TGFB1-ZEB2 and its role in acquired platinum resistance and EMT in TNBC. Our findings suggest that GPX3 is a promising biomarker and potential therapeutic target for the diagnosis, treatment, and prognosis of high-risk TNBC patients.
由于缺乏有效的靶向治疗方法以及获得性耐药的高可能性，三阴性乳腺癌（TNBC）仍然是全球影响女性的最致命癌症之一。研究TNBC对铂类化疗耐药的机制并确定新的治疗靶点是当务之急。
比较三种TNBC细胞系中GPX3的表达水平、顺铂敏感性和活性氧生成，以阐明GPX3与铂耐药之间的关系。对GPX3敲低细胞进行RNA测序和生物信息学分析，揭示其对应激相关信号通路和TGFB1的调控。使用蛋白质免疫印迹、RNA干扰、共聚焦显微镜和抑制剂处理进一步研究GPX3对TGFB1的调控。利用乳腺癌微阵列和TCGA数据库分析GPX3、TGFB1和ZEB2表达水平之间的相关性。使用小鼠异种移植模型研究GPX3对TNBC中铂敏感性的影响。
在侵袭性更强的TNBC细胞中，GPX3表达上调，促进对基于顺铂的化疗的耐药性。RNA测序显示，GPX3的缺失导致与促肿瘤信号通路相关的基因表达模式减少。验证实验证实，获得性顺铂耐药中TGFB1的上调高度依赖于GPX3。进一步研究表明，TGFB1-ZEB2轴通过上皮-间质转化（EMT）介导铂耐药和转移。此外，铂处理增加了GPX3和TGFB1的表达及分泌，它们的缺失增强了TNBC细胞对铂的敏感性。我们确定了GPX3-TGFB1-ZEB2调控轴，并在临床样本中发现三者的表达呈正相关。我们的研究还表明，在铂处理的小鼠模型中，GPX3敲低抑制了TNBC肿瘤生长。
本研究揭示了由GPX3-TGFB1-ZEB2介导的信号通路及其在TNBC获得性铂耐药和EMT中的作用。我们的研究结果表明，GPX3是高危TNBC患者诊断、治疗和预后的有前景的生物标志物和潜在治疗靶点。
