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 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.Growth factor signalling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAP kinase) axes enhances oestrogen receptor activity and frequently underlies endocrine resistance in breast tumours 1,2,6 . Water-only fasting or plant-based diets that are simultaneously low in calories, sugar and protein and proportionally high in fat (fasting-mimicking diets (FMDs)) reduce circulating growth factors such as insulin and IGF1 2,6,7 . Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of oestrogen therapy (ET) and delay endocrine resistance.Low-serum, low-glucose cell culture conditions designed to mimic the effects of fasting or FMD (referred to as short-term starvation, STS) increased the anti-tumour activities of tamoxifen and fulvestrant in HR + /HER2breast cancer (BC) cell lines, and similar results were obtained in mouse xenografts of the same cell lines subjected to weekly cycles of fasting or FMD (Fig. 1a, Extended Data Figs. 1, 2a, b). STS also increased the anti-tumour activity of tamoxifen in tumour organoids from patients with HR + BC 8 , and weekly FMD cycles prevented acquired resistance to tamoxifen in mice (Extended Data Fig. 2c, d). Enhancement of ET activity through STS was dependent on the reduction in serum, but not glucose, as adding back glucose to the growth medium did not affect the observed potentiation (Extended Data Fig. 3a).In mice, besides increasing β-hydroxybutyrate levels (Extended Data Fig. 3b) and lowering blood glucose (from 6.3 ± 0.6 mmol l −1 to 4.1 ± 0....

A high-fat diet: an unexpected role in preventing the metastatic seeding of colorectal cancer

“…HFD treatment could be widely used in the management of CRC–PC to reduce economic pressure and the side effects during treatment. This finding overturns the traditional view that a HFD may lead to the deterioration of cancer, 5 and provides a novel concept and potential therapies for preventing CRC–PC. In addition, early and timely immune enhancement through drugs may achieve similar effects of HFD therapy.…”

Fasting-mimicking diet plus chemotherapy in breast cancer treatment

“…In tumor-bearing mice, cycles of fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as FMDs, synergize with cytotoxic ChT or other antitumor therapies to slow down tumor growth 2 , 3 . At the same time, fasting/FMD protect normal tissues from ChT-induced toxicity 4 , 5 and boosts ChT-induced CD8+ T cell intratumor infiltration 2 .…”

“…These effects are mainly mediated by fasting/FMD-induced reduction of blood glucose, insulin and insulin-like growth factor 1 (IGF-1) concentration 4 , 5 . Notably, murine models of BC are exquisitely sensitive to the FMD when compared to other tumor types 2 , 3 . Therefore, the DIRECT trial, which investigated the FMD efficacy in reducing ChT-induced toxicities and in increasing pCR rates in HER2- BC patients, was timely and based on solid preclinical evidence.…”

Energy and caloric restriction, and fasting and cancer: a narrative review

“…Recently, Caffa et al showed that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or an FMD enhanced the endocrine therapeutics activity of tamoxifen and fulvestrant by lowering circulating IGF1, insulin, and leptin and by inhibiting AKT-mTOR signaling [47]. The authors also showed that in patients with hormone-receptorpositive breast cancer receiving estrogen therapy, cycles of an FMD cause metabolic changes like those observed in mice.…”