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Article | Open Access

Apple polyphenol phloretin inhibits type Ⅱ glucose transporter and enhances anti-HER2 antibody drug binding as an adjuvant treatment for HER2-positive breast cancer

Han-Sheng Changa,1, Tzu-Chun Chengb,1, Shih-Hsin Tuc,1, Pei-Han Liaoa, Yu-Ching Leed, Chi-Tang Hoe, Min-Hsiung Panf, Li-Ching Chena(), Yuan-Soon Hob()
Department of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung 404, Taiwan, China
Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 404, Taiwan, China
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, China
Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan, China
Department of Food Science, Rutgers University, New Jersey 08901, USA
Institute of Food Sciences and Technology, National Taiwan University, Taipei 10617, Taiwan, China

1 These authors contributed equally to this work.

Peer review under responsibility of Beijing Academy of Food Sciences.

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Abstract

This study presents novel findings on the potential of phloretin, an apple polyphenol, to enhance the effectiveness of anti-human epidermal growth factor receptor-2 (HER2) antibody therapy in HER2-positive breast cancer patients. Our research reveals that phloretin inhibits type Ⅱ glucose transporter (GLUT2) activity, significantly reducing cancer cell glucose uptake. We confirmed the overexpression of GLUT1 and GLUT2 mRNA in paired human breast tumor tissues, with GLUT2 overexpression associated explicitly with poorer survival rates in breast cancer patients. Treatment with phloretin was observed to increase the interaction between GLUT2 and HER2 proteins, attenuate glycolysis, and enhance the binding affinity of anti-HER2 antibody drugs to target human breast cancer cells. Furthermore, the efficacy of the combination therapy involving phloretin and antibody drugs was reaffirmed in a cell-derived xenograft tumor animal model, particularly in suppressing the growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. These significant findings suggest that targeting GLUT2 activity with phloretin in combination with anti-HER2 antibody drugs may help mitigate the development of drug-resistant breast cancer, offering valuable insights for enhancing tumor treatment strategies and contributing to developing more effective therapies.

Keywords

Type Ⅱ glucose transporter (GLUT2)PhloretinHuman epidermal growth factor receptor 2-intracellular domain (HER2-ICD)TrastuzumabTrastuzumab-resistance

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Food Science and Human Wellness
Volume 14 Issue 4,
April 2025
Article number: 9250251
DOI: 10.26599/FSHW.2024.9250251
Cite this article:
Chang H-S, Cheng T-C, Tu S-H, et al. Apple polyphenol phloretin inhibits type Ⅱ glucose transporter and enhances anti-HER2 antibody drug binding as an adjuvant treatment for HER2-positive breast cancer. Food Science and Human Wellness, 2025, 14(4): 9250251. https://doi.org/10.26599/FSHW.2024.9250251
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