The overall objectives of this proposal are to evaluate the concepts that low doses of different micronutrients used together may be more effective than high doses of a single micronutrient and that combining micronutrient interaction with hormonal factors may improve chemopreventive activity since they probably have different mechanisms of action. Carcinogenesis of the mammary gland is unique in that two distinct types of cancers occur, hormone dependent and independent. The use of different classes of agents (i.e., each perhaps specific for the type of cancers that occur) would appear to be a reasonable approach to preventing breast cancer. Using this rationale, studies are proposed to evaluate the effect on mammary cancer prevention of combining hormone, retinyl acetate and selenium treatments. It would be desirable if considerable overlap of these agents occurred (e.g. retinyl acetate is thought to be effective in preventing both hormone dependent and independent cancers). The proposed experiments will use the methylnitrosourea (MNU)-induced mammary cancer model in female Sprague-Dawley rats. The chemopreventive agents used will be short-term, high-dose estrogen plus progesterone, and low doses of retinyl acetate and sodium selenite. Although a major effort of each study is to determine the effect of the agents on prevention of mammary cancers, the possible toxicity of combining treatments will also be extensively investigated. Many classes of compounds have been shown to have chemopreventive activity, but their toxicity precludes their clinical use. The specific studies are designed to develop chemopreventive strategies that will both decrease the susceptibility of the mammary gland to carcinogens (i.e., prevent initiation) and prevent the progression and/or promotion of initiated cells to frank carcinomas. A final experiment is presented that will determine the effect of combining hormones, retinyl acetate, and selenium on reproductive and lactational performance. If chemoprevention of breast cancer is to be advocated in a young population, the agents used must not interfere with these physiological functions.
