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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

Han-Sheng Changa,1, Tzu-Chun Chengb,1, Shih-Hsin Tuc,d,1, Chih-Hsiung Wuc,1, You-Cheng Liaoe, Jungshan Change, Min-Hsiung Panf, Li-Ching Chena(), Yuan-Soon Hob()
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

1 These authors contributed equally to this work.

Peer review under responsibility of Tsinghua University Press.

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Highlights

• By inhibiting the t-DARPP/p95-HER2 complex, Quercetin can act as an adjuvant drug of Trastuzumab to alleviate the drug resistance in HER2+ breast cancer cells. The novelty and significance of this study are summarized as follows:

• This study confirmed that higher DARPP-32 and t-DARPP mRNA and protein levels are detected in HER2+ breast cancer tissues.

• This study demonstrated that the HER2 intracellular domain (HER2-ICD, p95-HER2) detected in breast cancer cells positively correlates with t-DARPP protein expression.

• This PDX mice model study demonstrated that the t-DARPP/p95-HER2 interaction is a potential diagnostic marker that could help clinicians identify patients resistant to Trastuzumab therapy (Non-responder).

• This study confirmed that Quercetin attenuated Trastuzumab resistance by inhibiting the t-DARPP expression and downregulating p95-HER2 -mediated signal activation (Responder).

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Abstract

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.

Keywords

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

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Food Science and Human Wellness
Volume 13 Issue 5,
September 2024
Pages 2653-2667
DOI: 10.26599/FSHW.2022.9250213
Cite this article:
Chang H-S, Cheng T-C, Tu S-H, et al. Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer. Food Science and Human Wellness, 2024, 13(5): 2653-2667. https://doi.org/10.26599/FSHW.2022.9250213
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