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Quercetin inhibits truncated isoform of dopamine-and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

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Food Science and Human Wellness 2024年第5期13卷 2653-2667页

作者： Han-Sheng chang Tzu-Chun Cheng Shih-Hsin Tu Chih-Hsiung Wu You-Cheng Liao jungshan chang Min-Hsiung Pan Li-Ching Chen Yuan-Soon Ho Department of Biological Science&Technology College of Life SciencesChina Medical UniversityTaichung 406TaiwanChina Institute of Biochemistry and Molecular Biology College of Life SciencesChina Medical UniversityTaichung 406TaiwanChina Department of Surgery School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 110TaiwanChina Department of Surgery Taipei Medical University HospitalTaipei 110TaiwanChina Graduate Institute of Medical Sciences College of MedicineTaipei Medical UniversityTaipei 110TaiwanChina Institute of Food Sciences and Technology National Taiwan UniversityTaipei 106TaiwanChina

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor *** evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor *** established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer ***,there is no response from the ***,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell *** found that quercetin effectively reduced t-DARPP expression in HER2+BC *** t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase *** conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.

关键词： p95-Human epidermal growth factor receptor 2 (HER2) HER2-positive breast cancer Quercetin Trastuzumab resistance Truncated isoform of dopamine-and cAMPregulated phosphoprotein

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