The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice

J Nutr Biochem. 2012 Oct;23(10):1230-7. doi: 10.1016/j.jnutbio.2011.07.003. Epub 2011 Dec 30.


Aromatase is responsible for the rate-determining reaction in estrogen synthesis and is a prime target for treating estrogen-receptor-positive breast cancer. Previous in vitro study has demonstrated that apigenin (APG), naringenin (NGN) and hesperetin (HSP) are three of the most potent natural aromatase inhibitors. Because the enzyme inhibition could potentially block breast cancer development, we employed an established postmenopausal breast cancer model to examine the chemopreventive effect of these flavonoids in vivo. Athymic mice were ovariectomized and transplanted with aromatase-overexpressing MCF-7 cells. Dietary administration of HSP at 1000 ppm and 5000 ppm significantly deterred the xenograft growth, while a null effect was observed in mice treated with APG or NGN. Further study illustrated that plasma estrogen in HSP-treated mice was reduced. Messenger RNA expression of the estrogen-responsive gene pS2 was also decreased in the tumors of mice treated with 1000 and 5000 ppm HSP. On the other hand, western analysis indicated that cyclin D1, CDK4 and Bcl-x(L) were reduced in the tumors. This study suggested that HSP could be a potential chemopreventive agent against breast carcinogenesis through aromatase inhibition.

MeSH terms

  • Animals
  • Aromatase / genetics
  • Aromatase / metabolism*
  • Aromatase Inhibitors / pharmacology*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Citrus / chemistry*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism
  • Estradiol / blood
  • Estrogens / blood
  • Female
  • Hesperidin / pharmacology*
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Ovariectomy / veterinary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism


  • Aromatase Inhibitors
  • Bcl2l1 protein, mouse
  • Ccnd1 protein, mouse
  • Cdkn1c protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p57
  • Estrogens
  • RNA, Messenger
  • bcl-X Protein
  • Cyclin D1
  • Estradiol
  • Hesperidin
  • Aromatase
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • hesperetin