CALORIE INTAKE DURING MAMMARY DEVELOPMENT INFLUENCES CANCER RISK - LASTING INHIBITION OF C3H HEOU MAMMARY TUMORIGENESIS BY PERIPUBERTAL CALORIE RESTRICTION/

To test for a relationship between peripubertal calorie intake, mammar y development, and tumorigenesis, weanling C3H/HeOu mice were separate d into 3 groups: fed diet either ad libitum (AL) and designated group AL (n = 60); fed a similar, calorie-restricted (CR) diet only during m ammary development when 4-12 weeks old and then subsequently fed ad li bitum when greater than or equal to 13 weeks old (group CR(4-12), n = 24); or continuously calorie restricted (group CR, n = 60). Eight week s of peripubertal calorie restriction provided CR(4-12) mice with last ing protection from mammary tumorigenesis (P = 0.004) and lowered cumu lative tumor incidence by 33% compared to AL mice. Sustained calorie r estriction of group CR mice further reduced mammary tumor incidence co mpared to both AL (P = 0.000001) and CR(4-12) mice (P = 0.009). Calori e intake significantly influenced mammary development and cellular pro liferation. Compared to the mammary development of AL mice, calorie re striction reduced the diameter of ductal end buds (189 mu m compared t o 146 mu m; P < 0.01), lowered the end bud [H-3]thymidine labeling ind ex from greater than or equal to 20 to less than or equal to 13% (P < 0.001), delayed end bud migration and mammary glandular growth (P < 0. 01), reduced alveolar budding (P < 0.001), reduced the proportion of a lveoli containing at least one [H-3]thymidine labeled cell from greate r than or equal to 50 to less than or equal to 22% (P < 0.001), and lo wered the alveolar [H-3]thymidine labeling index of labeled alveoli fr om greater than or equal to 14 to less than or equal to 7% (P < 0.001) . These findings link peripubertal calorie intake, mammary development , and carcinogenic risk, and show that the abrogation of mammary tumor igenesis by calorie restriction is partially attributable to influence s on mammary development.