Activating Peroxisome Proliferator-Activated Receptor γ Mutant Promotes Tumor Growth <i>In vivo</i> by Enhancing Angiogenesis

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in a variety of cancer cells. 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 PPARgamma signaling in breast cancer, we compared the function of a constitutively active PPARgamma (PgammaCA) mutant with the wild-type PPARgamma in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARgamma or PgammaCA were implanted into immunocompetent FVB mice. Enhanced tumor growth was observed in PgammaCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor, c-Kit, CD133, and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARgamma; PgammaCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration; conversely, immunodepletion of Angptl4 reduced PgammaCA-mediated cellular migration. Collectively, these studies suggest that activated PPARgamma induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo.