gw-501516 and Carcinoma--Ductal

The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease.

Topics: Animals; Carcinogenesis; Carcinoma, Ductal; Epithelium; Female; Gene Expression; Genes, erbB-2; Inflammation; Inflammatory Breast Neoplasms; Mammary Neoplasms, Experimental; Metabolomics; Mice; Mice, Transgenic; Phenotype; PPAR delta; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Receptors, Progesterone; Thiazoles; TOR Serine-Threonine Kinases

Peroxisome proliferator-activated receptor (PPAR) represents a ligand-dependent nuclear receptor family that regulates multiple metabolic processes associated with fatty acid beta-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 PPARgamma and PPARdelta agonists in a progestin- and carcinogen-induced mouse mammary tumorigenesis model. Animals treated with the PPARgamma agonist GW7845 exhibited a moderate delay in tumor formation. In contrast, animals treated with the PPARdelta 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 PPARgamma agonist expressed estrogen receptor-alpha in luminal transit cells, suggesting increased ductal progenitor cell expansion. Tumors from mice treated with the PPARdelta agonist exhibited increased PPARdelta 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 PPARdelta activation. These results indicate that PPARdelta and PPARgamma agonists produce diverse, yet profound effects on mammary tumorigenesis that give rise to distinctive histopathologic patterns of tumor differentiation and tumor development.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Adenosquamous; Carcinoma, Ductal; Carcinoma, Squamous Cell; Cell Differentiation; Disease Progression; Female; Gene Expression Profiling; Mammary Neoplasms, Experimental; Mice; Oxazoles; PPAR delta; PPAR gamma; Thiazoles; Tyrosine