Hybridized microarray slides were scanned with the Agilent DNA Microarray Scanner G2505C at a 5-m resolution with the manufacturers software (Agilent ScanControl 8.1.3). with this paper. 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 diet3C5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKTCmTOR 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)CAKTCmammalian target of rapamycin MK-5172 hydrate (mTOR) and mitogen-activated protein kinase (MAP kinase) axes enhances oestrogen receptor activity and frequently underlies endocrine resistance in breast tumours1,2,6. Water-only fasting or plant-based diets that Rabbit Polyclonal to Smad1 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 IGF12,6,7. 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+/HER2? breast 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, MK-5172 hydrate ?,2a,2a, ?,b).b). STS also increased the anti-tumour activity of tamoxifen in tumour organoids from patients with HR+ BC8, and weekly FMD cycles prevented acquired resistance to tamoxifen in mice (Extended Data Fig. 2c, ?,d).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). Open in a separate window Fig. 1 a, Growth of MCF7 xenografts in 6C8-week-old female BALB/c nude mice treated with ad libitum diet (control, CTR; = 6), weekly 48-h FMD (= 6), tamoxifen (TMX; = 6), fulvestrant (FULV; = 8), or combined TMX + FMD (= 8) or FULV + FMD (= 10). b, Changes in serum IGF1, C-peptide and leptin concentration in female 6C8-week-old BALB/c nude mice treated with fasting or FMD (or ad libitum diet) with or without TMX or FULV. Serum was collected at the end of the fast or FMD. c, MK-5172 hydrate Six-to-eight-week-old female BALB/c nude mice were inoculated with MCF7 cells; when tumours became palpable, mice were randomized to be treated with ad libitum diet (= 6), FULV (= 6), FULV plus weekly FMD (= 6), FULV plus weekly FMD plus intraperitoneal (i.p.) insulin (ins.; = 5), IGF1 (= 5), leptin (lept.; MK-5172 hydrate = 5) or combined insulin + IGF1 + leptin (FRFs comb.; =.
