Evidence from animal models and experimental human breast cancer cell growth in nude mice indicates that omega-6 fatty acids (n-6 FAs) stimulate growth and metastasis of mammary cancer, whereas omega-3 (n-3) FAs may exert an inhibitory effect. An understanding of the influence of different types of FAs on the biological behavior of human breast cancer cells is essential for the rational development of dietary interventions for disease prevention, and as adjuvant therapy after surgery. To this end, a series of studies is proposed utilizing a nude mouse model for human breast cancer cell metastasis. These will compare the effects of feeding diets containing different levels and proportions of n-6 and n-3 FAs on MDA-MB-435 cell growth at the primary (inoculation) site and on metastasis. Mechanistic studies will focus on (a) the role of the n-6 FA-derived eicosanoids in modulating tumor cell growth and expression of metastatic potential, and (b) on the inositol phospholipid signal transduction pathway. Prostaglandin and leukotrienes will be assayed directly in solid tumors, and [14C]-labelled n-6 FAs employed to assess their incorporation into membrane phospholipids of recultured primary and metastatic cells, the subsequent mobilization of arachidonate, and its utilization for eicosanoid production. The rates of inositol phospholipid hydrolysis, diacylglycerol production, and phospholipase C and protein kinase C Activities will be compared in cells from primary and metastatic tumors, which developed in mice from the various dietary groups.
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