Related Experiment Video
Updated: May 12, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2
Qingyi Hu1, Qianzhi Chen1, Wen Yang1
1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
This study identifies GPX3 as a key driver of platinum resistance in triple-negative breast cancer (TNBC). Targeting GPX3 may overcome resistance and improve treatment outcomes for TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) presents a significant global health challenge due to limited effective therapies and high rates of acquired resistance.
- Platinum-based chemotherapy is a common treatment, but resistance mechanisms in TNBC require urgent investigation to identify new therapeutic targets.
Purpose of the Study:
- To investigate the role of GPX3 in platinum resistance in TNBC.
- To elucidate the signaling pathways involved in GPX3-mediated platinum resistance and epithelial-mesenchymal transition (EMT).
Main Methods:
- Compared GPX3 expression, cisplatin sensitivity, and ROS production in TNBC cell lines.
- Utilized RNA sequencing, bioinformatics, Western blotting, RNA interference, and mouse xenograft models.
- Analyzed GPX3, TGFB1, and ZEB2 correlations in clinical breast cancer samples and TCGA database.
Main Results:
- GPX3 upregulation promotes cisplatin resistance and is linked to increased invasiveness in TNBC cells.
- The GPX3-TGFB1-ZEB2 axis drives platinum resistance and metastasis via EMT.
- GPX3 depletion enhances platinum sensitivity, and its knockdown inhibits tumor growth in vivo.
Conclusions:
- GPX3 is a critical mediator of acquired platinum resistance and EMT in TNBC through the GPX3-TGFB1-ZEB2 pathway.
- GPX3 represents a promising biomarker and therapeutic target for improving diagnosis, treatment, and prognosis in high-risk TNBC patients.
More Related Videos
06:54Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
09:40Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
