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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045127-06
Application #
3188117
Study Section
Experimental Virology Study Section (EVR)
Project Start
1986-09-01
Project End
1994-08-31
Budget Start
1991-09-01
Budget End
1994-08-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Li, H W; Zhao, W; Sarkar, N H (1994) Dietary regulation of mammary tumorigenesis in RIII/Sa mice: investigation of a possible mechanism. Cancer Lett 79:199-211
Imai, S; Okumoto, M; Iwai, M et al. (1994) Distribution of mouse mammary tumor virus in Asian wild mice. J Virol 68:3437-42
Xu, L; Haga, S; Imai, S et al. (1994) Cloning in a plasmid of an MMTV from a wild Chinese mouse: sequencing of the viral LTR. Virus Res 33:167-78
Aguan, K; Scott, J; See, C G et al. (1994) Characterization and chromosomal localization of the human homologue of a rat AMP-activated protein kinase-encoding gene: a major regulator of lipid metabolism in mammals. Gene 149:345-50
Hossain, A; Sarkar, A; Sarkar, N H (1991) Mixed inocula of mouse mammary tumour cell subpopulations result in changes of organ-specific metastasis. Clin Exp Metastasis 9:501-15
Hossain, A; Sarkar, N H (1991) Colonization characteristics of a murine mammary tumor cell line that metastasizes frequently to the heart. Clin Exp Metastasis 9:351-61
Sarkar, N H (1990) Genetic diversity of spontaneously developed primary and metastatic mammary tumor cells in mice. Cancer Commun 2:379-86
Siddique, H R; Sarkar, N H (1990) The interaction of a c-Jun/Fos related protein factor with the U3 sequences of the mouse mammary tumor virus LTR. Biochem Biophys Res Commun 172:348-56