There is growing experimental and epidemiological evidence to suggest that mammary tumorigenesis may be controlled by the quantity and type of dietary fat consumed. Lipids, such as arachidonate (20:4(n-6)) and its oxygenated metabolites (collectively termed eicosanoids) play an important role in cell growth, motility and invasion of mammary tumors. 20:3(5,11,14), a novel fatty acid similar to 20:4(n-6) but lacking the internal 8 double bond essential for leukotriene and prostaglandin synthesis, is a potent and unique tool for reducing 20:4(n-6) levels in phospholipid and for studying arachidonate- or eicosanoid-dependent processes. Importantly, in studies with mice, 20:3(5,11,14) was found to reduce 20:4(n-6) levels even more than the (n-3) fatty acids found in fish oils, and in distinct contrast to (n-3) fatty acids, to selectively replace arachidonate in phosphatidylinositol. Cell lines established from human breast cancers provide in vitro models for breast cancer in various stages of progression. These cell lines will be used to examine the effects of 20:3(5,11,14) and other nutritionally related unsaturated fatty acids on growth and invasiveness of human breast cancer cells and to develop a model system of investigate the mechanism of its action. Several transmembrane signaling systems, which have been proposed to play vital roles in growth regulation of mammary carcinoma and are thought to be modulated directly by 20:4(n-6) or eicosanoids, will be examined. These will include changes in cellular levels of Ca2+, cAMP, metabolism of phosphoinositides, and activation of phospholipase C, phospholipase D, and protein kinase C. The effects of 20:3(5,11,14) and several other nutritionally relevant fatty acids on chemotactic responsiveness and invasiveness of human breast cancer cells will be compared in Boyden chamber chemoinvasion, chemotaxis, and Matrigel outgrowth assays. To shed light on the relevance of these findings to clinical situations, 20""""""""3(5,11,14) and other related unsaturated fatty acids will be evaluated in nude mouse models of mammary tumor growth and tumor metastasis. In addition, a mouse carcinogenesis model, BALB/cfC3H mice carrying a spontaneously arising mammary tumor, will also be utilized to determine whether this non-methylene interrupted fatty acid may be effective in the prevention of breast cancer in this model system. Since long term experiments indicate that the feeding of some oils containing 20:3(5,11,14) are not lethal and does not substantially reduce appetite, weight, or activity, it is anticipated that this study will provide the scientific basis for progression to clinical trials of 20:3(5,11,14) for the prevention and treatment of breast cancer.
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