The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter

J Food Drug Anal. 2018 Jan;26(1):221-231. doi: 10.1016/j.jfda.2017.03.009. Epub 2017 Apr 18.


Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10-150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10-150 μM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.

Keywords: Apple polyphenol; Breast cancer; Glucose transporter 2; Phloretin; Triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Breast Neoplasms / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Female
  • Glucose Transporter Type 2 / metabolism*
  • Humans
  • Malus / chemistry*
  • Mice
  • Phloretin / chemistry
  • Phloretin / pharmacology*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Phytogenic
  • Glucose Transporter Type 2
  • Plant Extracts
  • Phloretin

Grants and funding

This study was supported by the Health and Welfare Surcharge on tobacco products (MOHW105-TDU-B-212-134001) and by the Ministry of Science and Technology (MOST 104-2320-B-038-066-MY2).