Supplementary Data - PDF file 3276K, Supplementary Figure 1. Characterization of MMTV-PPAR{delta} transgenic mice. Supplementary Figure 2. Metabolomic analysis Supplementary Figure 3. Signaling pathways associated with PPRE-containing genes. activated in MMTV-PPAR{delta} mice treated with GW501516 for 11 weeks. Supplementary Table 1. Antibodies for IHC and western blotting. Supplementary Table 2. List of primers for qRT-PCR analysis. Supplementary Table 3. Gene expression preferentially altered in MMTV-PPAR{delta} mice treated with GW501516 and everolimus. Supplementary Table 4. Gene expression preferentially altered in MMTV-PPARd mice treated with GW501516 for 11 weeks. Supplementary Table 5. Gene expression preferentially altered in MMTV-PPARd mice. Supplementary Table 6. Gene expression preferentially altered in wild-type mice treated with GW501516 for 11 weeks.
ARTICLE ABSTRACT
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. Cancer Res; 73(14); 4349–61. ©2013 AACR.
