Defining the Molecular Actions of Dietary Fatty Acids in Breast Cancer: Selective Modulation of Peroxisome Proliferator-Activated Receptor Gamma
KENTUCKY UNIV RESEARCH FOUNDATION LEXINGTON
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Stark differences in the actions of linoleic acid LAA an omega-6 fatty acid and eicosapentaenoic acid EPA an omega-3 fatty acid on breast cancer tumors have been described. We propose that transactivation of peroxisome proliferators-activated receptor gamma PPARy mediates the physiological effects of different dietary fatty acids on breast cancer. PPARy plays a role in the development and progression of breast cancer tumors. We have shown that individual ligands of PPARy can selectively activate PPARy in three different ways. Selective activation of PPARy by a single ligand occurs between tissue types and between individual breast cancer cell lines. Also unique ligands selectively activate PPARy within a single cell type. We propose that fatty acids will elicit their effects on breast cancer cells in a similar manner. Using both pharmaceutical and molecular approaches we have demonstrated that PPARy serves as a molecular target for both LAA and EPA. Our data shows that fatty acids utilize PPARy to activate a PPAR response element reporter system and that the receptor is both sufficient and necessary to observe this response. Also EPA treatment increases the ability of PPARy to bind to DNA. Furthermore through multiple approaches we have determined that fatty acids do not need to be converted to prostaglandins but themselves can function as PPARy ligands. To date we have determined that both LAA and EPA act as PPARy agonists. The objective of future studies will be to demonstrate that LAA and EPA act as selective PPARy modulators SPARMs in breast cancer cells. We hypothesize that though both LAA and EPA are PPARy agonists they function as SPARMs by causing unique gene expression and that this is in part the mechanism responsible for the different physiological actions of these fatty acids. Most recently we have demonstrated that rosiglitizone a PPARy ligand also serves as an agonist of the estrogen receptor in breast cancer cells.
- Anatomy and Physiology
- Medicine and Medical Research