Bonorden, Melissa J.L.

To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG). Age of prostate tumor detection (~33 wk) and death (~43 wk) was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet.

Abstract Intermittent caloric restriction (ICR) provides greater prevention of mammary tumor (MT) development than chronic caloric restriction (CCR). Here we assessed the impact of a high-fat diet on this protective effect in relation to serum IGF-I, leptin and adiponectin. At 10 wk of age MMTV-TGF-α female mice were assigned to AL (ad libitum 23% fat calories), ICR (3-wk of 50% caloric restriction with 2× protein, fat, vitamins and minerals followed by 3-wk of 100%AL mice's consumption) and CCR (calorie/nutrient intake matched to ICR for each 6-wk cycle) groups (n=45/group). Food intakes were determined daily. Body weights, MT palpation and MT measurements were done weekly. Mice were followed until MT burden necessitated euthanasia or they reached 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum samples were obtained at baseline, euthanasia and cycles 5, 8, and 11 during restriction and refeeding for ICR mice. Food intakes for ICR and CCR mice were 24.2% and 24.3% lower than AL mice (p<0.05). Body weights of ICR mice fluctuated in response to their calorie intake resulting in a significant difference among the groups. Final body, mammary and internal fat pad weights of AL mice were heaviest, followed by CCR and ICR-refed mice. ICR-restricted mice weights were the lowest. 66.7% of AL mice developed 1–5 MTs/mouse (grade 1–4). 52.3% of CCR mice had 1–3 MTs/mouse (grade 1–4). Only 4.4% of ICR mice developed 1 MT/mouse (grade 2). ICR-Restricted mice had significantly higher terminal serum IGFBP-3 and lower IGF-I and IGF-1/IGFBP-3 ratio than AL mice. There were no differences for CCR and ICR-Refed mice compared to either AL or ICR-Restricted groups. ICR-Restricted mice had significantly lower serum leptin and significantly higher terminal adiponectin and adiponectin/leptin ratio compared to AL, CCR and ICR-Refed mice. There were no differences in terminal serum measurements between mice with MTs versus those without MTs. IGF-I of AL and CCR mice did not change with age whereas for ICR mice IGF-1 was reduced during restriction periods. AL mice had the highest leptin levels across the study follow by CCR. For ICR mice leptin fluctuated in response to calorie intake, higher in refeeding vs restriction. Adiponectin levels for AL and CCR mice over time were similar. ICR mice had higher adiponectin levels when restricted vs refed. The adiponectin/leptin ratio of AL, CCR and ICR-refed mice was dramatically lower across the study compared with baseline but for ICR-restricted mice it was similar. These results indicate that ICR provides greater protection compared to CCR to prevent MT development even when a high fat diet is fed during refeeding. This was reflected by decreased MT incidence and MT burden and aggressiveness. Serum IGF-I, adiponectin and leptin were significantly affected by periods of 50% restriction providing a milieu conducive to reduced MT development. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A110.

Abstract The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. Cancer Prev Res; 4(4); 568–81. ©2011 AACR.

Abstract The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. Ten-week-old MMTV-TGF-α female mice were assigned to ad libitum–fed (AL; AIN-93M diet), ICR [3-week 50% caloric restriction using AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3 weeks of daily 100% AL consumption of AIN-93M (∼75% of AL for each 6-week cycle)], and CCR (calorie and nutrient intake matched for each 6-week ICR cycle) groups. Half of the mice from each group were sacrificed at 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum was obtained at euthanasia and in cycles 1, 3, 5, 8, and 11. MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICR-Restricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. There were no differences in terminal IGFBP-3. Final body, internal, and mammary fat pad weights correlated positively with IGF-I and negatively with IGFBP-3. Few changes were found for protein expression of IGF-IRα and IGFBP-3 in mammary tissue and MTs. During the study, IGF-I levels of ICR-Restricted mice were reduced, whereas refeeding allowed partial recovery. For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR.