Journal Article

Fasting-mimicking diet and hormone therapy induce breast cancer regression

Clevers, Hans, Mastracci, Luca, Provenzani, Alessandro, Zucal, Chiara, Mantero, Carolina, Nencioni, Alessio, Vellone, Valerio G., Zoppoli, Gabriele, Valdemarin, Francesca, Piazza, Silvano, Caffa, Irene, Sukkar, Samir G., Brandhorst, Sebastian, Ferrando, Lorenzo, Piacente, Francesco, Ballestrero, Alberto, Tagliafico, Alberto, Odetti, Patrizio, Passalacqua, Mario, Arrighi, Annalisa, Wei, Min, De Braud, Filippo, Cilli, Michele, Spagnolo, Vanessa, Becherini, Pamela, Salvadori, Giulia, Cea, Michele, Cortellino, Salvatore, Vernieri, Claudio, Gradaschi, Raffaella, Monacelli, Fiammetta, Driehuis, Else, Longo, Valter D., Cremonini, Anna Laura

2020

Overview

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 benefit 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet 3 – 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. In mice, periodic fasting or a fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a fasting-mimicking diet recreates the metabolic changes observed in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/89 / 38/39 / 38/61 / 38/77 / 631/67/1347 / 631/67/2327 / 64/60 / 82/1 / 82/51 / 82/80 / AKT protein / Animal models / Animals / Anticancer properties / Biological Factors - blood / Breast cancer / Breast Neoplasms - diet therapy / Breast Neoplasms - drug therapy / Breast Neoplasms - pathology / Care and treatment / Cell adhesion & migration / Cell cycle / Cooperation / Cyclin-dependent kinase / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Diet / Diet therapy / Diet Therapy - methods / Diet, Healthy - methods / Disease Models, Animal / Disease Progression / Drug Resistance, Neoplasm - drug effects / Early Growth Response Protein 1 - metabolism / EGR-1 protein / Endocrine therapy / Endometrium / Enzyme inhibitors / Estrogens / Fasting / Fasting - physiology / Female / Fulvestrant / Fulvestrant - administration & dosage / Fulvestrant - therapeutic use / Gene expression / Glucose / Hormone replacement therapy / Hormone therapy / Hormones / Humanities and Social Sciences / Humans / Hyperplasia / Insulin / Insulin - blood / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factors / Kinases / Leptin / Leptin - blood / MCF-7 Cells / Medical prognosis / Methods / Mice, Inbred NOD / Mice, SCID / Mimicry / multidisciplinary / Phosphorylation / Piperazines - administration & dosage / Piperazines - therapeutic use / Progesterone / Progesterone receptors / Proteins / PTEN Phosphohydrolase - metabolism / PTEN protein / Pyridines - administration & dosage / Pyridines - therapeutic use / Receptors / Receptors, Estrogen / Receptors, Progesterone / Science / Science (multidisciplinary) / Tamoxifen / Tamoxifen - adverse effects / Tamoxifen - therapeutic use / Therapy / TOR protein / Tumor necrosis factor-TNF / Tumors / Xenograft Model Antitumor Assays