The long term objective of this project is to determine how dietary fatty acids influence the progression of breast cancer. A secondary objective is to develop combinations of dietary interventions and pharmacological agents which suppress this progression in an appropriate animal model. The short term goals are: first, to explore further interrelations between dietary fatty acids, lipoxygenase products, and proteolytic enzyme expression in the invasive process; second, to extend these studies to include lipoxygenase product-mediated activation of protein kinase (PKC); third, to determine whether the poor invasive and metastatic capability of estrogen receptor positive breast cancer cell lines is related to a low level of 12-lipoxygenase (12-LOH) activity and impaired 12-hydroxyeicosa-tetraenoic acid (12-HETE) synthesis. The first specific aim will determine the effects of n-6 and n-3 fatty acids on the metastatic potential of MDA-MB-231 and MDA-MB-435 estrogen-independent human breast cancer cells in nude mice. The second specific aim is to test the hypothesis that estrogen independent breast cancer cells progress to a more highly metastatic phenotype that is associated with enhanced expression of vimentin and proteolytic activity as a consequence of an induction of 12-LOX activity through 12-HETE-mediated PKC activation. The applicant proposes to evaluate this hypothesis both in vitro and in vivo. In the proposed in vitro studies, breast cancer cell lines with different degrees of estrogen dependence and independence will be examined and compared for invasive activity, vimentin and protease expression, and PKC activity for the effects of the n-6 amino acids (LA and AA), also, 12-HETE will be assessed on the expression of these compounds of the metastatic phenotype. In addition, the same cell lines will be grown in the mammary fatpad of nude mice and the capacity for spontaneous metastases compared in vivo.
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