Fasting-mimicking diet and hormone therapy induce breast cancer regression.

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.

• Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco Piacente, Alberto Tagliafico, Michele Cilli, Luca Mastracci, Valerio G Vellone, Silvano Piazza, Anna Laura Cremonini, Raffaella Gradaschi, Carolina Mantero, Mario Passalacqua, Alberto Ballestrero, Gabriele Zoppoli, Michele Cea, Annalisa Arrighi, Patrizio Odetti, Fiammetta Monacelli, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Samir G Sukkar, Alessandro Provenzani, Valter D Longo, Alessio Nencioni
• Journal: Nature (Nature) Vol. 583 Issue 7817 Pg. 620-624 (07 2020) ISSN: 1476-4687 [Electronic] England
• PMID: 32669709 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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

Topics

• Animals
• Biological Factors (blood)
• Breast Neoplasms (diet therapy, drug therapy, 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, 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, therapeutic use)
• Pyridines (administration & dosage, therapeutic use)
• Receptors, Estrogen
• Receptors, Progesterone
• Tamoxifen (adverse effects, therapeutic use)
• Xenograft Model Antitumor Assays