Caloric restriction has been shown to inhibit proliferation of both spontaneous and chemically-induced tumors in mice and rats. We have shown that caloric restriction inhibits promotion of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors as well as sex hormone-independent colon tumors induced by 1,2- dimethylhydrazine in rats even in the face of a high fat diet. We propose to investigate the possibility that caloric restriction alters hormonal levels and receptors involved in host and tumor metabolism. Female Sprague-Dawley rats given DMBA will be fed control diets or diets in which calories are restricted by 25%. We will assay circulating levels of insulin, somatomedin C, epidermal growth factor (EGF), estradiol and prolactin. We will examine receptors for these factors in membranes of mammary tumors and normal tissues of rats fed control or calorie- restricted diets. In order to assess the causal relationship of reductions in insulin, somatomedin-C, EGF, estradiol and prolactin with decreased tumorigenesis during caloric restriction, we will subject rats given DMBA to caloric restriction and provide each of these growth factors by osmotic pump. Substrate uptake, which is influenced by several of the aforementioned growth factors, by tumors as well as control tissue from both dietary groups will be measured using 3-0- methylglucose, proline, octanoate, and beta hydroxybutyrate (as representatives of carbohydrate, protein, fat and ketone bodies, respectively). The proposed studies will examine an inter-related series of hormonal actions that may control tumor growth. We propose to study these mitogenic hormones, their receptors, and whether their effects are mediated through energy utilization by tumors themselves. These studies will identify factors controlling mammary tumor growth during the promotion stage and may have significance for understanding basic biological control mechanisms through which diet can influence susceptibility to cancer.
