The long-range goals of this project is to understand the mechanism(s) by which dietary calories and fat modulate murine mammary tumorigenesis and mammary tumor metastasis. From our recent work we know that there is a relationship between the dietary-induced modulation of MuMTV expression, prolactin secretion, and the development of hyperplastic alveolar nodules (HANs) and mammary tumors in mice. However, we do not know at which age dietary changes should be implemented, and for how long the altered diet should be maintained in order to lower the risk of breast cancer. We therefore propose to determine the effects of feeding mice alternately with a diet which results in a high incidence of breast cancer, and then with another diet which results in a low incidence of breast cancer, and vice versa, on the development of HANs and breast cancer. We will determine the effects of such dietary changes on the expression of MuMTV- RNA, proteins and virus particles, in the fatty acid composition of, and the prostaglandin production by, mammary tumors and the mammary glands of mice of various ages. We will also measure the amounts of serum prolactin in these mice. Furthermore, we will determine the tumorigenic potential of the small sized HANs that are developed in mice fed a low calorie low fat diet by transplanting them into mice fed a low calorie high fat or a high calorie low fat diet. Because of the known effects of fat on mammary tumorigenesis, we will determine, using our newly developed adult mouse mammary gland organ culture system, the effects of fatty acids on the development and/or involution of normal lobulo alveoli (LA) and HANs, prostaglandin biosynthesis, and the expression of MuMTV genes and/or gene products in the mammary glands of mice of different ages fed different diets. We also propose to determine the effects of different diets on mammary tumor metastasis, and to determine if there is a relationship between site-specific MuMTV integration, virus expression and tumor metastasis. In our studies we will use the techniques of histology, electron microscopy, molecular hybridization, radioimmunoassays and high pressure liquid chromatography. As a result of our proposed studies, we hope to understand how calories and fat affect the complex interaction between hormones, fatty acids, prostaglandins, and the mammary cells of mice of different ages, and how this interaction influences mammary tumorigenesis and mammary tumor metastasis.
