Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models
The effects of long-term nicotine exposure on the treatment of HER2-positive breast cancer have only been studied epidemiologically, leaving the molecular mechanisms unclear. Therefore, it's challenging for clinicians to devise effective treatments based on this correlation. Our investigation e...
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Elsevier
2025-04-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325004075 |
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| author | Yu-Hsuan Lin Yuan-Soon Ho Bu-Miin Huang You-Cheng Liao Tzu-Chun Cheng Ying-Chi Lin Shih-Hsin Tu Yun Yen Li-Ching Chen |
| author_facet | Yu-Hsuan Lin Yuan-Soon Ho Bu-Miin Huang You-Cheng Liao Tzu-Chun Cheng Ying-Chi Lin Shih-Hsin Tu Yun Yen Li-Ching Chen |
| author_sort | Yu-Hsuan Lin |
| collection | DOAJ |
| description | The effects of long-term nicotine exposure on the treatment of HER2-positive breast cancer have only been studied epidemiologically, leaving the molecular mechanisms unclear. Therefore, it's challenging for clinicians to devise effective treatments based on this correlation. Our investigation explores the effects of prolonged nicotine exposure on the interaction between α9-nAChR and HER2 in HER2-positive breast cancer cells, highlighting its impact on anti-HER2 drug therapy efficacy. We used fluorescence resonance energy transfer (FRET) analysis to compare HER2 + tumor samples from smokers and non-smokers, finding a more vital interaction between α9-nAChR and HER2 in non-smoker's breast tumor tissues. A simulated study on the breast cancer patient-derived xenograft (PDX) tumor mouse model (n = 6 per group) revealed that long-term nicotine exposure significantly reduced this interaction compared to controls. Due to the poorer response of low HER2 tumors to trastuzumab in clinical practice, most patients require combination chemotherapy and have a worse prognosis. Therefore, this study chose HER2-low PDX models to simulate nicotine exposure and explore treatment strategies. Mice subjected to prolonged nicotine exposure exhibited faster tumor growth and reduced trastuzumab efficacy compared to controls (*p < 0.05). Our results demonstrate that extended nicotine exposure weakens α9-nAChR and HER2 interaction, reducing the effectiveness of HER2-targeted therapy, fostering drug resistance, and underscoring the carcinogenic risks of nicotine. |
| format | Article |
| id | doaj-art-dcdabb65b3294b8bb5306f24906fe96a |
| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-dcdabb65b3294b8bb5306f24906fe96a2025-08-20T02:07:57ZengElsevierEcotoxicology and Environmental Safety0147-65132025-04-0129411807110.1016/j.ecoenv.2025.118071Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor modelsYu-Hsuan Lin0Yuan-Soon Ho1Bu-Miin Huang2You-Cheng Liao3Tzu-Chun Cheng4Ying-Chi Lin5Shih-Hsin Tu6Yun Yen7Li-Ching Chen8Department of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung 406040, TaiwanInstitute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406040, TaiwanDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Department of Biomedical Sciences, National Chung Cheng University, Chiayi 621301, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110031, TaiwanInstitute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406040, TaiwanDepartment of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung 406040, TaiwanDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, TaiwanTMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110301, TaiwanDepartment of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung 406040, Taiwan; Correspondence to: Department of Biological Science & Technology, China Medical University, No. 100, Section 1, Jingmao Rd., Beitun Dist., Taichung City 406040, Taiwan.The effects of long-term nicotine exposure on the treatment of HER2-positive breast cancer have only been studied epidemiologically, leaving the molecular mechanisms unclear. Therefore, it's challenging for clinicians to devise effective treatments based on this correlation. Our investigation explores the effects of prolonged nicotine exposure on the interaction between α9-nAChR and HER2 in HER2-positive breast cancer cells, highlighting its impact on anti-HER2 drug therapy efficacy. We used fluorescence resonance energy transfer (FRET) analysis to compare HER2 + tumor samples from smokers and non-smokers, finding a more vital interaction between α9-nAChR and HER2 in non-smoker's breast tumor tissues. A simulated study on the breast cancer patient-derived xenograft (PDX) tumor mouse model (n = 6 per group) revealed that long-term nicotine exposure significantly reduced this interaction compared to controls. Due to the poorer response of low HER2 tumors to trastuzumab in clinical practice, most patients require combination chemotherapy and have a worse prognosis. Therefore, this study chose HER2-low PDX models to simulate nicotine exposure and explore treatment strategies. Mice subjected to prolonged nicotine exposure exhibited faster tumor growth and reduced trastuzumab efficacy compared to controls (*p < 0.05). Our results demonstrate that extended nicotine exposure weakens α9-nAChR and HER2 interaction, reducing the effectiveness of HER2-targeted therapy, fostering drug resistance, and underscoring the carcinogenic risks of nicotine.http://www.sciencedirect.com/science/article/pii/S0147651325004075α9-nAChRHER2SmokingBreast cancerHerceptin resistancePatient-derived xenograft |
| spellingShingle | Yu-Hsuan Lin Yuan-Soon Ho Bu-Miin Huang You-Cheng Liao Tzu-Chun Cheng Ying-Chi Lin Shih-Hsin Tu Yun Yen Li-Ching Chen Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models Ecotoxicology and Environmental Safety α9-nAChR HER2 Smoking Breast cancer Herceptin resistance Patient-derived xenograft |
| title | Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models |
| title_full | Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models |
| title_fullStr | Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models |
| title_full_unstemmed | Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models |
| title_short | Mechanisms of reduced efficacy of HER2-targeted therapy in HER2-low breast cancer by long-term nicotine exposure in patient-derived xenograft mouse tumor models |
| title_sort | mechanisms of reduced efficacy of her2 targeted therapy in her2 low breast cancer by long term nicotine exposure in patient derived xenograft mouse tumor models |
| topic | α9-nAChR HER2 Smoking Breast cancer Herceptin resistance Patient-derived xenograft |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325004075 |
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