Involvement of Human Estrogen Related Receptor Alpha 1 (hERR 1) in Breast Cancer and Hormonally Insensitive Disease

Abstract : In human primary breast tumors, ERR alpha mRNA levels were greater than or similar to those of ER alpha in 24% of unselected tumors, with steroid receptor-negative tumors exhibiting the highest ERR alpha levels. Additionally, ERR alpha mRNA levels statistically correlated with ErbB2 levels. Thus, ERR alpha mRNA was abundantly expressed in a subset of tumors that tended to lack functional ER alpha and expressed ErbB2 at high levels. Hence, ERR alpha may be an unfavorable biomarker. In MCF-7 cells, which exhibit low ErbB2 levels, ERR alpha functioned primarily as an active repressor, down-modulating estrogen response element (ERE) -regulated transcription through competition with ER alpha for binding EREa. In BT-474 cells, which overexpress ErbB2, ERR alpha constitutively activated ERE-regulated transcription, regardless of the presence of antiestrogens, and potentiated the agonist-effects of ER alpha ligands on transcription when levels of the coactivator GRIPl were not limiting. Also, ERR alpha DNA-binding sites were identified in the promoters of multiple genes involved in breast cancer. ErbB2 signaling - likely led to activation of ERR alpha through phosphorylation, since disruptors of ErbB2 signaling, such as anti-HER2 antibodies and the MAPK kinase inhibitor U0126, blocked ERR alpha mediated transcription. Additionally, MAPK phosphorylated ERR alpha in vitro. Therefore, ERR alpha's (phosphorylated) status may indicate sensitivity to hormonal and ErbB2-based therapies.