Timeless, a novel oestrogen receptor co-activator with a critical role in Breast Cancer (#44)
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.
1. Ali and Coombes (2002). Endocrine responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2: 101-110.
2. Green and Carroll (2007). Oestrogen-receptor mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer 7: 713-719.
3. Tozlu-Kara et al. (2007). Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen. J Mol Endocrinol 39:305-18.