PGC-1α Promotes the Growth of ErbB2/Neu-Induced Mammary Tumors by Regulating Nutrient Supply

Cancer cells display an increased reliance on glycolysis despite the presence of sufficient oxygen levels to support mitochondrial functions. In this study, we asked whether ameliorating mitochondrial functions in cancer cells might limit their proliferative capacity. Specifically, we increased mitochondrial metabolism in a murine cellular model of ErbB2/Neu-induced breast cancer by ectopically expressing the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), a master regulator of mitochondrial metabolism. As predicted, ErbB2/Neu cells ectopically expressing PGC-1 alpha displayed an increased level of mitochondrial metabolism and reduced proliferative capacity in vitro, compared with controls. In contrast, ErbB2/Neu cells ectopically expressing PGC-1 alpha formed larger tumors in vivo. These tumors exhibited increased concentrations of glucose and the angiogenic factor VEGF as well as higher expression of ErbB2/Neu compared with controls. We discovered that ErbB2/Neu levels were sensitive to nutrient availability, such that reduced glucose concentrations resulted in diminished ErbB2/Neu protein levels. Therefore, our data indicate that PGC-1 alpha prevents the nutrient-mediated downregulation of ErbB2/Neu in tumors by increasing glucose supply. Mechanistic investigations revealed that the regulation of ErbB2/Neu levels by glucose was mediated by the unfolded protein response (UPR). Incubation of ErbB2/Neu-induced breast cancer cells in limited glucose concentrations or with drugs that activate the UPR led to significant reductions in ErbB2/Neu protein levels. Also, ErbB2/Neu-induced tumors ectopically expressing PGC-1 alpha displayed lowered UPR activation compared with controls. Together, our findings uncover an unexpected link between PGC-1 alpha-mediated nutrient availability, UPR, and ErbB2/Neu levels. Cancer Res; 72(6); 1538-46. (C) 2012 AACR.