Defining the Molecular Actions of Dietary Fatty Acids in Breast Cancer: Selective Modulation of Peroxisome Proliferator-Activated Receptor Gamma. Addendum; Final rept. 30 Sep 2006-8 Apr 2008

摘要

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 (PPAR.) mediates the physiological effects of different dietary fatty acids on breast cancer. PPAR. plays a role in the development and progression of breast cancer tumors. We have shown that individual ligands of PPAR. can selectively activate PPAR. in three different ways. Selective activation of PPAR. by a single ligand occurs between tissue types and between individual breast cancer cell lines. Also, unique ligands selectively activate PPAR. 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 PPAR. serves as a molecular target for both LAA and EPA. Our data shows that fatty acids utilize PPAR. 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 PPAR. 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 PPAR. ligands. To date, we have determined that both LAA and EPA act as PPAR. agonists. The objective of future studies will be to demonstrate that LAA and EPA act as selective PPAR. modulators (SPARMs) in breast cancer cells. We hypothesize that, though both LAA and EPA are PPAR. 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. We have also demonstrated that rosigli.