Key Points
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When oestrogen binds to the oestrogen receptor (ER), the ER dimerizes and translocates into the nucleus, where it recruits co-activators or co-repressors, as well as chromatin-remodelling factors, to oestrogen response elements (EREs) on target gene promoters in order to activate or repress transcription.
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Multiple signalling pathways downstream of receptor tyrosine kinases (such as ERBB2, epidermal growth factor receptor 1 and insulin-like growth factor 1 receptor) coordinately regulate the dynamics of ER-mediated transcriptional regulation.
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The availability of ER co-activators and ER co-repressors and their post-translational modifications determine the selectivity and timing of target gene expression. Many ER co-activators have enzymatic activities, including acetylation, methylation, demethylation and phosphorylation.
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Several ER co-activators also regulate ubiquitin-dependent proteolysis and modify ER. For example, MAPK mediates ER phosphorylation at S294 and cyclin E–cyclin-dependent kinase 2 (CDK2) phosphorylates ER at S341 to prime the interaction of ER with S-phase kinase-associated protein 2, which is the substrate- recognition subunit of the SKP1–cullin 1–F-box protein ubiquitin ligase complex. This drives target gene transcription and mediates ubiquitin-dependent ER proteolysis.
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These findings provide considerable insight into the subtleties of hormone-regulated steroid receptor stability and function that could ultimately lead to novel therapeutic strategies based on the manipulation of hormone receptor stability.
Abstract
Oestrogen receptor-α (ERα) is a master transcription factor that regulates cell proliferation and homeostasis in many tissues. Despite beneficial ERα functions, sustained oestrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Oestrogen–ERα interaction can trigger post-translational ERα modifications through crosstalk with signalling pathways to promote transcriptional activation and ubiquitin-mediated ERα proteolysis, with co-activators that have dual roles as ubiquitin ligases. These processes are reviewed herein. The elucidation of mechanisms whereby oestrogen drives both ERα transactivation and receptor proteolysis might have important therapeutic implications not only for breast cancer but also potentially for other hormone-regulated cancers.
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Change history
23 December 2013
In Figure 2 on page 30 of this Review the oestrogen receptor (ER) dimer on the left-hand side was erroneously shown to simultaneously bind to SP1 and AP1 transcription factors. The ubiquitylated ER that enters the proteasome is most likely an unliganded monomer and not an oestrogen-bound ER dimer as originally shown in the figure. Tyrosine phosphorylation of ER was shown as being Y357 instead of Y537 and the text in the central blue box which stated “Dual role co-activators mediate ER degradation coupled to target gene activation” should have read “Dual role ER co-activators promote ER target gene activation coupled to ER proteolysis”. All of these corrections have been made online.
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Acknowledgements
This work was supported by US National Institutes of Health grant R01CA123415 (J.M.S.) and by US Department of Defense pre-doctoral grant W81XWH-11-1-0097 (W.Z.). The authors thank M. Lippman, D. El-Ashry, Z. Nawaz, C. Perou and laboratory members for helpful discussions. The authors apologize for omissions in citations and coverage: strict space and citation limits preclude the inclusion of many important past and recent works.
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Zhou, W., Slingerland, J. Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy. Nat Rev Cancer 14, 26–38 (2014). https://doi.org/10.1038/nrc3622
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DOI: https://doi.org/10.1038/nrc3622
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