Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells

Estrogen-related receptor alpha (ERR alpha) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERR alpha has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERR alpha a putative negative prognostic factor, but we have recently found that knock-down of its expression retards tumor growth in a xenograft model of this disease. The specific aspects of ERR alpha function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1 alpha as a protein ligand to regulate ERR alpha activity, we analyzed the effects of this receptor on gene expression in the ER alpha-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERR alpha target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERR alpha in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. The induction of VEGF results from the interaction of ERR alpha with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERR alpha-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERR alpha is expressed and provide validation for its use as a therapeutic target in cancer. (C) 2009 Elsevier Ltd. All rights reserved.