More recently, we have turned our attention to the role of the ligand-dependent nuclear peroxisome proliferator-activated receptor (PPAR) family in chemoprevention and cell fate determination during mammary tumorigenesis. Using a mammary carcinogenesis model we developed, we have found that PPARγ agonist GW7845 delays tumor formation, whereas, PPARδ agonist GW501516 accelerates tumor development, which is associated with activation of and association with PDK1. Surprisingly, evaluation of these drugs in mice heterozygous for stem cell antigen-1 (Sca-1), a marker of stem and early progenitor cells, has shown that both PPAR agonists markedly blocked tumorigenesis. These results suggest that the phenotype resulting from loss of one Sca-1 allele is exquisitely sensitive to a common pathogenic process that is sensitive to PPARδ and PPARγ activation.  Recent gene array analyses suggest that Sca-1 heterozygous mice may be prone to an inflammatory phenotype. Our lab has also developed a new transgenic mouse model expressing dominant-negative PPARγ in the mammary gland, which has been used to clearly demonstrate that PPARγ agonists exert their chemopreventive activity directly on mammary epithelium. These mice are also highly susceptible to mammary carcinogenesis, suggesting that PPARγ activation by endogenous dietary ligands has a normal protective function against tumorigenesis.

Other studies are examining mammary stem and progenitor cell expansion by the use of GSK3β inhibitors that activate Wnt signaling, a pathway involved in stem cell self-renewal.  Thus, our current research program focuses on the inter-relationships between PPAR activation and the Sca-1 signaling pathway, and their roles in modulating stem cell expansion, susceptibility to carcinogenesis and the activity of chemopreventive agents.

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