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ERK/MAPK regulates ERRγ 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 (ERRγ) 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. mRNA 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. ERRγ transcriptional activity was assessed by dual‐luciferase promoter–reporter assays. We show that ERRγ protein levels are affected by the activation state of ERK/mitogen‐activated protein kinase, and mutation of consensus ERK target sites impairs ERRγ‐driven transcriptional activity and TAM resistance. These findings shed new light on the functional significance of ERRγ in ER+ breast cancer, and are the first to demonstrate a role for kinase regulation of this orphan nuclear receptor.