Fasting-mimicking diet and hormone therapy induce breast cancer regression

Nature. 2020 Jul;583(7817):620-624. doi: 10.1038/s41586-020-2502-7. Epub 2020 Jul 15.

Abstract

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Factors / blood
  • Breast Neoplasms / diet therapy*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Diet Therapy / methods*
  • Diet, Healthy / methods
  • Disease Models, Animal
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects
  • Early Growth Response Protein 1 / metabolism
  • Fasting / physiology*
  • Female
  • Fulvestrant / administration & dosage
  • Fulvestrant / therapeutic use*
  • Humans
  • Insulin / blood
  • Insulin-Like Growth Factor I / metabolism
  • Leptin / blood
  • MCF-7 Cells
  • Mice, Inbred NOD
  • Mice, SCID
  • PTEN Phosphohydrolase / metabolism
  • Piperazines / administration & dosage
  • Piperazines / therapeutic use
  • Pyridines / administration & dosage
  • Pyridines / therapeutic use
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tamoxifen / adverse effects
  • Tamoxifen / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Biological Factors
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Insulin
  • Leptin
  • Piperazines
  • Pyridines
  • Receptors, Estrogen
  • Receptors, Progesterone
  • insulin-like growth factor-1, mouse
  • Tamoxifen
  • Fulvestrant
  • Insulin-Like Growth Factor I
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • palbociclib