About 70% of all breast cancers are oestrogen receptor (ER)-positive and proliferate in response to oestrogen stimulation. The SERM tamoxifen has been successfully used for both pre- and post-menopausal women for many years. However, some tumours are de novo resistant, whilst others will eventually develop resistance to tamoxifen over time. Despite the deepening understanding of the mechanisms of resistance, developing therapeutic solutions to combat tamoxifen resistance remains a clinical challenge. Recently, the human homologue of Timeless (a Drosophila gene involved in circadian rhythm) was shown to clearly discriminate between patients who relapse from tamoxifen therapy and those who are successfully treated, although the molecular basis of this association is unknown. Here, we showed that human Timeless is an ERα co-activator. Using co-immunoprecipitation and ERα-responsive luciferase reporter assays, Timeless directly binds to ERα and increases its transcriptional activity. 17β-oestradiol-induced expression of ERα target genes GREB1, pS2 and cmyc is enhanced by an overexpression of Timeless and inhibited by a knockdown of Timeless. Finally, increased Timeless expression promotes agonistic activity of ER-bound tamoxifen in MCF-7 cells. These data, the first to link Timeless to steroid hormone function, provide a mechanistic basis for clinical associations between Timeless expression and tamoxifen resistance, and suggest that patients whose breast tumours express high levels of Timeless may be better served by alternative strategies to SERMs.

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