ERK / MAPK regulates ERR γ expression, transcriptional activity and receptor‐mediated tamoxifen resistance in ER + breast cancer

Selective estrogen receptor modulators such as tamoxifen ( TAM ) significantly improve breast cancer‐specific survival for women with estrogen receptor‐positive ( ER +) disease. However, resistance to TAM remains a major clinical problem. The resistant phenotype is usually not driven by loss or mutation of the estrogen receptor; instead, changes in multiple proliferative and/or survival pathways over‐ride the inhibitory effects of TAM . Estrogen‐related receptor γ ( ERR γ) is an orphan member of the nuclear receptor superfamily that promotes TAM resistance in ER + breast cancer cells. This study sought to clarify the mechanism(s) by which this orphan nuclear receptor is regulated, and hence affects TAM resistance. m RNA and protein expression/phosphorylation were monitored by RT ‐ PCR and western blotting, respectively. Site‐directed mutagenesis was used to disrupt consensus extracellular signal‐regulated kinase (ERK) target sites. Cell proliferation and cell‐cycle progression were measured by flow cytometric methods. ERR γ transcriptional activity was assessed by dual‐luciferase promoter–reporter assays. We show that ERR γ protein levels are affected by the activation state of ERK /mitogen‐activated protein kinase, and mutation of consensus ERK target sites impairs ERR γ‐driven transcriptional activity and TAM resistance. These findings shed new light on the functional significance of ERR γ in ER + breast cancer, and are the first to demonstrate a role for kinase regulation of this orphan nuclear receptor.