Protective effect of intermittent versus chronic calorie restriction on mammary tumor development in relationship to prospective IGF-1 serum concentrations in MMTV-TGF-α mice Free

B4

Numerous studies indicate that chronic caloric restriction (CCR) provides a protective effect on chemically-induced and spontaneous mammary tumor (MT) development in rodents. Recently, intermittent caloric restriction (ICR) was reported to be more protective than CCR in transgenic mouse models that develop MTs. One growth factor considered to mediate tumorigenesis is IGF-I. Here we compare prospective serum IGF-I levels in relationship to mammary tumorigenesis for these two modes of calorie restriction.
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 >At 8 wk of age 225 MMTV-TGF-α female mice had ad libitum access to AIN-93M diet. At 10 wk they were assigned to AL (ad libitum 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), and CCR (fed a diet to match calorie and nutrient intake for each 6-wk ICR cycle, ~ 75% of AL consumption) groups. Food intakes were determined daily. Body weights, palpation and tumor measurements were done weekly. Mice were followed until MT burden necessitated euthanasia or they reached terminal endpoints of 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum samples were obtained at euthansia and in cycles 1, 3, 5, 8, and 11 from cohorts corresponding to the 1^st, 2^nd and 3^rd weeks of restriction and refeeding for ICR mice to relate levels of IGF-1 to the appearance of palpable MT.
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 >Cumulative food intakes for ICR and CCR mice were 24.8% and 22.6% lower, than AL mice (p<0.05).
 >Body weights fluctuated in response to calorie intake during the study for ICR mice and there was an overall significant difference among the groups. Final body weights, mammary and internal fat pad weights of AL mice were heaviest, followed by CCR and IR-refed mice with similar weights (p>0.05) while ICR-restricted mice weights were the lowest. 68.3% of AL mice developed 1-6 MTs/mouse (grade 1-3), 36.2% of CCR mice had 1-2 MTs/mouse (grade 1-3) and only 8.2% of ICR mice developed 1 MT/mouse (grade 1-2). There were no differences for time to tumor detection and MT weights among the groups. Terminal serum IGF-1 concentration of AL mice was higher (p<0.05), than for CCR, ICR-refed, and ICR-restricted mice, which had lower (p<0.05) IGF-I than CCR and ICR-refed mice. There was a positive correlation between terminal IGF-1 and body weights (r=0.95) and mammary fad pad weights (r=0.95) for all mice. IGF-1 serum concentrations across the study were higher prior to MT detection from the earliest time point for AL and CCR mice. However, this was not found for ICR mice.
 >These results confirm that ICR provides greater protection compared to CCR with respect to prevention of MT development. Additionally, tumor burden and aggressiveness were reduced in ICR mice. The IGF-1 axis appears to be involved in MT development but its specific role in the protective effect of calorie restriction remains to be determined. It is anticipated that ongoing mammary fat pad and MT analyses will provide additional insights into why ICR is superior to CCR with respect to prevention of mammary tumorigenesis.
 >(Support: NIH CA 101858 and The Hormel Foundation).