Stein Rebecca A, Gaillard Stéphanie, McDonnell Donald P
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710, United States.
J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):106-12. doi: 10.1016/j.jsbmb.2009.02.010. Epub 2009 Mar 3.
Estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor family of transcription factors. In addition to its function as a metabolic regulator, ERRalpha has been implicated in the growth and progression of several malignancies. In the setting of breast cancer, not only is ERRalpha 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 ERRalpha function that are responsible for its actions in breast cancer, however, remain unclear. Using the coactivator PGC-1alpha as a protein ligand to regulate ERRalpha activity, we analyzed the effects of this receptor on gene expression in the ERalpha-positive MCF-7 cell line. This analysis led to the identification of a large number of potential ERRalpha target genes, many of which were subsequently validated in other breast cancer cell lines. Importantly, we demonstrate in this study that activation of ERRalpha 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 ERRalpha with specific ERR-responsive elements within the VEGF promoter. These findings suggest that ERRalpha-dependent induction of VEGF may contribute to the overall negative phenotype observed in tumors in which ERRalpha is expressed and provide validation for its use as a therapeutic target in cancer.
雌激素相关受体α（ERRα）是核受体转录因子家族的一个孤儿成员。除了作为代谢调节因子的功能外，ERRα还与多种恶性肿瘤的生长和进展有关。在乳腺癌中，ERRα不仅是一个假定的负性预后因素，而且我们最近发现，在该疾病的异种移植模型中，敲低其表达会延缓肿瘤生长。然而，ERRα在乳腺癌中发挥作用的具体功能方面仍不清楚。我们使用共激活因子PGC-1α作为蛋白配体来调节ERRα活性，分析了该受体对雌激素受体α阳性MCF-7细胞系中基因表达的影响。该分析鉴定出大量潜在的ERRα靶基因，其中许多随后在其他乳腺癌细胞系中得到验证。重要的是，我们在本研究中证明，在几种不同的乳腺癌细胞系中激活ERRα会导致VEGF mRNA表达显著增加，这种活性转化为VEGF蛋白分泌增加。VEGF的诱导是由于ERRα与VEGF启动子内特定的ERR反应元件相互作用所致。这些发现表明，ERRα依赖性诱导VEGF可能导致在表达ERRα的肿瘤中观察到的总体负性表型，并为其作为癌症治疗靶点的应用提供了验证。
