PPARδ as a Metabolic Initiator of Mammary Neoplasia and Immune Tolerance

Figure 1

Interactions between inflammation, metabolism, and mTOR signaling in the mammary gland of MMTV-PPARδ mice. PPARδ activates PPRE-containing genes associated with metabolism (Olah, Ptgs2, Pla2, and Pld), invasion (Mmp12, Klk6), and inflammation (S100a8/9, Saa1/2/3). Arachidonic acid (AA) is a substrate for Ptgs2 and is a constituent of phosphatidylcholine (PC) required for prostaglandin synthesis. Lysophosphatidylcholine (LPC) is generated from PC by phospholipase A2 (Pla2), and lysophosphatidic acid (LPA) and phosphatidic acid (PA) are generated by phospholipase D (Pld). LPA stimulates mTOR through a G protein-coupled receptor, and PA directly activates mTOR. The mTOR inhibitor RAD001 (everolimus) inhibits tumorigenesis in this animal model. The net result is an increase in inflammation, extracellular matrix remodeling, immune suppression, and neoplasia. Adapted from [31].