Ligand-Activated Interaction Of Ppar Delta With C-Myc Governs The Tumorigenicity Of Breast Cancer

Peroxisome proliferator-activated receptor (PPAR) delta is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic potential remains to be determined. In our study, we show that ligand-activated PPAR delta forms a complex with the proto-oncogene product c-Myc. The interaction of PPAR delta with c-Myc affected the transcriptional activity of c-Myc and the expression of its target genes. The PPAR delta-dependent regulation of c-Myc activity was associated with decreased tumorigenicity in breast cancer cells. Administration of the PPAR delta ligand GW501516 inhibited tumor growth in xenograft model mice bearing MDA-MB-231 cells stably expressing wild-type PPAR delta, but not those expressing dominant-negative PPAR delta, by interfering with c-Myc function through protein-protein interaction. Our results indicating that PPAR delta forms an antitumorigenic complex with c-Myc in the presence of ligand suggest a potential role of PPAR delta in breast cancer development.