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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外文摘要：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 cAMP-regulated 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.

外文关键词：

p95-Human epidermal growth factor receptor 2(HER2)HER2-positive breast cancerQuercetinTrastuzumab resistanceTruncated isoform of dopamine-and cAMP-regulated phosphoprotein

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

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作者单位：

Department of Biological Science&Technology,College of Life Sciences,China Medical University,Taichung 406,Taiwan,China

Institute of Biochemistry and Molecular Biology,College of Life Sciences,China Medical University,Taichung 406,Taiwan,China

Department of Surgery,School of Medicine,College of Medicine,Taipei Medical University,Taipei 110,Taiwan,China

Department of Surgery,Taipei Medical University Hospital,Taipei 110,Taiwan,China

Graduate Institute of Medical Sciences,College of Medicine,Taipei Medical University,Taipei 110,Taiwan,China

Institute of Food Sciences and Technology,National Taiwan University,Taipei 106,Taiwan,China

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基金：

National Science and Technology Council of Taiwan

项目编号：

出版年：

2024

DOI：

10.26599/FSHW.2022.9250213

食品科学与人类健康(英文)

CSTPCD

ISSN：

年,卷(期)：2024.13(5)