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Peroxisome Proliferator-Activated Receptor and Agonists Differentially Alter Tumor Differentiation and Progression during Mammary Carcinogenesis

¹ Department of Oncology, Georgetown University, Washington, District of Columbia; ² Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois; and ³ Division of Chemoprevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Robert I. Glazer, Department of Oncology, Georgetown University School of Medicine, Room W318, Research Building, 3970 Reservoir Road, Northwest, Washington, DC 20057. Phone: 202-687-8324; Fax: 202-687-7505; E-mail: glazerr{at}georgetown.edu.

Peroxisome proliferator-activated receptor (PPAR) represents a ligand-dependent nuclear receptor family that regulates multiple metabolic processes associated with fatty acid ß-oxidation, glucose utilization, and cholesterol transport. These and other receptor-mediated actions pertain to their role in hypolipidemic and antidiabetic therapies and as potential targets for cancer chemopreventive agents. The present study evaluated the chemopreventive activity of two highly potent and selective PPAR and PPAR agonists in a progestin- and carcinogen-induced mouse mammary tumorigenesis model. Animals treated with the PPAR agonist GW7845 exhibited a moderate delay in tumor formation. In contrast, animals treated with the PPAR agonist GW501516 showed accelerated tumor formation. Significantly, tumors from GW7845-treated mice were predominantly ductal adenocarcinomas, whereas tumors from GW501516-treated animals were adenosquamous and squamous cell carcinomas. Gene expression analysis of tumors arising from GW7845- and GW501516-treated mice identified expression profiles that were distinct from each other and from untreated control tumors of the same histopathology. Only tumors from mice treated with the PPAR agonist expressed estrogen receptor- in luminal transit cells, suggesting increased ductal progenitor cell expansion. Tumors from mice treated with the PPAR agonist exhibited increased PPAR levels and activated 3-phosphoinositide–dependent protein kinase-1 (PDK1), which co-associated, suggesting a link between the known oncogenic activity of PDK1 in mammary epithelium and PPAR activation. These results indicate that PPAR and PPAR agonists produce diverse, yet profound effects on mammary tumorigenesis that give rise to distinctive histopathologic patterns of tumor differentiation and tumor development.

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