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

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 

机构地区：[1]Department of Biological Science&Technology,College of Life Sciences,China Medical University,Taichung 406,Taiwan,China [2]Institute of Biochemistry and Molecular Biology,College of Life Sciences,China Medical University,Taichung 406,Taiwan,China [3]Department of Surgery,School of Medicine,College of Medicine,Taipei Medical University,Taipei 110,Taiwan,China [4]Department of Surgery,Taipei Medical University Hospital,Taipei 110,Taiwan,China [5]Graduate Institute of Medical Sciences,College of Medicine,Taipei Medical University,Taipei 110,Taiwan,China [6]Institute of Food Sciences and Technology,National Taiwan University,Taipei 106,Taiwan,China

出　　处：《Food Science and Human Wellness》2024年第5期2653-2667,共15页食品科学与人类健康（英文）

基　　金：The National Science and Technology Council of Taiwan funded this study.

摘　　要：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 progression.To 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 tissues.We 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 assays.Instead,there is no response from the responder.Furthermore,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 migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In 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 

分 类 号：R285[医药卫生—中药学]