Intermittent calorie restriction decreases mammary tumor development in MMTV-TGF-α mice

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Numerous studies have shown that chronic caloric restriction (CCR) provides a protective effect on chemically-induced and spontaneous mammary tumor (MT) development in rodents. This is demonstrated by decreased MT incidence and/or increases in latency and decreased tumor burden. Recently, intermittent caloric restriction (ICR) was reported to be more protective than CCR in two transgenic mouse models that develop MTs.

Here we used 225 MMTV-TGF-α female mice to further explore and compare how similar overall degrees of caloric restriction implemented by ICR vs CCR provide protection against mammary tumorigenesis. Mice were assigned to AL (ad libitum fed AIN-93M diet), ICR (3-wk of 50% caloric restriction of AIN-93M-mod diet with 2x protein, fat, vitamins, and minerals followed by 3-wk of 100% AL mice’s consumption of AIN-93M for each corresponding 3-wk), and CCR (fed a diet mixture to match calorie and nutrient intake for each 6-wk ICR cycle) groups (n=75/group). Protocols were initiated at 8 wk of age and mice were followed until they reached terminal endpoints of 79 (end of final restriction) and 82 (end of final refeeding) wk of age or until disease or tumor burden necessitated euthanasia. Serum samples were obtained from all mice over the study (cycles 1, 3, 5, 8, and 11 from three cohorts corresponding to the first, second and third weeks of restriction and refeeding of ICR) to relate levels of IGF-1, leptin and adiponectin to the appearance of palpable tumor. Terminal serum samples were also obtained.Cumulative food intakes for ICR and CCR mice were 24.8% and 22.6% lower, than AL mice (p<0.05). Final body weights and retroperitoneal + parametrial and mammary fat pad weights of AL mice were the heaviest, followed CCR and IR-refed with similar weights (p>0.05), while ICR-restricted mice weights were the lightest. 69.5% of AL, 30.3% of CCR and 6.2% of ICR mice developed MTs. Tumor-bearing AL mice developed 1 to 6 MTs with histological grade ranging from 1-3; CCR mice had 1 to 2 MTs classified as grade 1-3; and ICR mice only had 1 MT/per mouse (grade 1-2). There was no statistical difference for MT weights among groups. At euthanasia AL mice had serum IGF-1 levels significantly higher than of CCR (p<0.01), ICR-refed (p<0.01), and ICR-restricted (p<0.01) mice, but there were no significant differences between ICR and CCR mice. Ongoing analyses include determining longitudinal relationship of serum IGF-1, leptin and adiponectin to MT development and caloric restriction, as well as evaluating apoptotic, proliferation, leptin and adiponectin related proteins in MT and fat tissue. These results confirm that intermittent calorie restriction provides a greater protective effect for the prevention of MTs compared to chronic restriction. (Support: NIH CA 101858 and The Hormel Foundation).