Effect of energy restriction on tissue size regulation during chemically induced mammary carcinogenesis

Energy restriction (ER) has documented beneficial effects on numerous diseases including cancer, yet the mechanism(s) that accounts for these effects is unknown. Experiments were designed to determine the effect of ER: (i) on the growth and development of the mammary gland; (ii) on the growth of carcinomas induced in the mammary gland by treatment with 1-methyl-1-nitrosourea (MNU); (iii) on rates of cell proliferation and apoptosis in pre-malignant and malignant mammary lesions. Mammary carcinogenesis was induced in female Sprague-Dawley rats by the i.p. administration of MNU (50 mg MNU/kg body wt) at 21 days of age. Rats were randomized to one of four dietary treatment groups: ad libitum fed or restriction of calorie intake to 90, 80 or 60% of ad libitum intake. ER reduced the ductal extension of the mammary gland into the fat pad in proportion to its effect on growth measured as body weight, however, the reduction in ductal branching, breast density and carcinoma volume by ER was greater than its effect on body weight. An animal's breast density was predictive of its carcinogenic response, irrespective of the level of ER imposed. While ER inhibited cell proliferation and induced apoptosis in pre-malignant and malignant mammary gland lesions, the magnitude of these effects make it unlikely that they fully account for the protective effects of ER against mammary carcinogenesis.