Peroxisome proliferator-activated receptor δ and γ agonists differentially alter tumor differentiation and progression during mammary carcinogenesis

Yuzhi Yin, Robert G. Russell, Luis E. Dettin, Renkui Bai, Zhi Liang Wei, Alan P. Kozikowski, Levy Kopleovich, Robert I. Glazer

Research output: Contribution to journalArticlepeer-review

Abstract

Peroxisome proliferator-activated receptor (PPAR) represents a ligand-dependent nuclear receptor family that regulates multiple metabolic processes associated with fatty acid β-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 PPARγ and PPARδ agonists in a progestin- and carcinogen-induced mouse mammary tumorigenesis model. Animals treated with the PPARγ agonist GW7845 exhibited a moderate delay in tumor formation. In contrast, animals treated with the PPARδ 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 PPARγ agonist expressed estrogen receptor-α in luminal transit cells, suggesting increased ductal progenitor cell expansion. Tumors from mice treated with the PPARδ agonist exhibited increased PPARδ levels and activated 3-phosphoinositide-dependent protein kinase-1 (PDKI), which co-associated, suggesting a link between the known oncogenic activity of PDK1 in mammary epithelium and PPARδ activation. These results indicate that PPARδ and PPARγ agonists produce diverse, yet profound effects on mammary tumorigenesis that give rise to distinctive histopathologic patterns of tumor differentiation and tumor development.

Original languageEnglish (US)
Pages (from-to)3950-3957
Number of pages8
JournalCancer Research
Volume65
Issue number9
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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