Cross-talk between Estrogen Receptor-related Receptor alpha (ERRalpha) and Estrogen Receptor (ERalpha) pathways.

Orphan nuclear receptor estrogen-related receptor alpha (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of ERRα in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERα) and ERRα initially suggested that these receptors may share similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. Since a small molecule ligand has not been identified for ERRα, its transcriptional activity in these studies was induced using its known coactivator PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) as a protein ligand. Both wild-type PGC1, as well as ERRa-specific variant (PGC1 2x9) were used to activate ERRa. Non-NR-dependent activities of PGC-1α were controlled for using a variant PGC-1α in which the leucines within the NR-interacting domain had been mutated to alanines (L2L3M). Beta-galactosidase (BGAL) overexpression was used as a non-specific background control. Activation of endogenous ER was achieved by treatment with 10 nM estadiol. Keywords: Response to stimulus MCF7 cells were infected with adenovirus overexpressing one of the four proteins (PGC1 WT, PGC1 2x9, PGC1 L2L3 and BGAL); Twelve hours post infection cells were then treated with either 10 nM estradiol (E2)or ethanol vehicle for 12 hours. Each combination of infection and treatment was was repeated three times in three independent experiments. A total of 23 samples are presented. Two replicates instead of three are shown for PGC1 WT E2 for technical reasons.