PPARγ, originally cloned as a transcription factor involved in fat cell differentiation, is activated by endogenous ligands, such as fatty acids produced by sterol response element binding protein 1 (SREBP1) and fatty acids synthase (FASN) pathways and synthetic ligands including the thiazolidinediones (TZD). PPARγ is expressed in a variety of cancer cells. Independent lines of evidence support a role for PPARγ to either inhibit or promote tumorigenesis. Human breast cancer is associated with ErbB2 amplification or overexpression in >30% of patients. Although PPARγ is reduced in ErbB2 induced tumor, the role of PPARγ in growth control of ErbB2-induced tumorigenesis is poorly understood. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation. To investigate the role of activated PPARγ signaling in breast cancer, we compared the function of a constitutively active PPARγ (PγCA) mutant with the wild-type PPARγ in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARγ or PγCA were implanted into immune competent FVB mice. Enhanced tumor growth was observed in PγCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor (vWF), c-Kit, CD133 and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARγ. PγCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration and conversely immuno-depletion of Angptl4 reduced PγCA-mediated cellular migration. Collectively, these studies suggest that activated PPARγ induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1720.