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Oestrogen receptors pathways to oestrogen responsive elements: The transactivation function-1 acts as the keystone of oestrogen receptor (ER)β-mediated transcriptional repression of ERα

Abstract : Oestrogen receptors (ER)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (EREs) located in a number of gene promoters. Transient transfection of different luciferase reporter vectors 3xEREs-Vit, 2xEREs-tk and ERE-C3 showed that the transactivation capacity of both ER subtypes was influenced by 1) the nature of the inducer (oestradiol (E2), phyto- and anti-oestrogen (AE)), 2) the structure of the promoter (nucleotidic sequence, number of ERE, length of the promoter sequence) and 3) the cell line (containing endogenous ER (MCF-7) or in which ER was stably expressed (MDA-MB-231-HE-5 (ERalpha+) or MDA-MB-231-HERB (ERbeta+)). ER subtype did not display the same efficacy on the different constructions in the presence of E2 and of AE according to the cell (e.g. in MCF-7 cells: tk>>Vit>>C3 approximately 0 while in MDA-MB-231 cells: Vit>>tk approximately C3). E2 response was higher in MCF-7 cells, probably due to higher ER expression level (maximal at 10(-10)M instead of 10(-8)M for E2 in HE-5 cells). Finally, the same ligand could exert opposite activities on the same promoter according to the ER isoform expressed: in the MDA-MB-231 cells, AE acted as inducers of the C3 promoter via ERbeta whereas ERalpha/AE complexes down-regulated this promoter. Approximately 70% of breast tumours express ER and most tumour cells coexpress both ER isotypes. Thus, different types of ER dimers can be formed in such tumours (ERbeta or ERalpha homodimers or ERalpha/ERbeta heterodimers). We therefore studied the influence of the coexistence of the two ERs on the ligand-induced transcriptional process following transient transfection of ERalpha in ERbeta+ cells, and inversely ERbeta in ERalpha+ cells. ERbeta-transfection inhibited the E2- and genistein-induced ERalpha-dependent transcription on all promoters in all cell lines except C3 in MCF-7; this inhibitory effect was lost following transfection of ERbeta deleted of its AF-1 (ERbeta-AF-2). These results suggest that the dominant negative properties of ERbeta are mainly due to its AF-1 function. Interestingly, transfection of an ERbeta-AF-2 construct into MCF-7 cells potentiated the transcription inhibitory capacity of 4-OH-tamoxifen (OHT) on the Vit and tk promoters. Thus, (1) OHT exerts an agonistic activity through the AF-1 function of ER and (2) expression of ERbeta in breast cancer cells seems to favour the AE treatment. Contrary to ERbeta, ERalpha-transfection had little effect on ERbeta transactivation capacity in HERB cells. Finally, the ratio ERalpha/ERbeta constitutes one decisive parameters to orientate the transcriptional mechanism of a target gene in the presence of agonist as well as of antagonist ligands.
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Angélique Gougelet, Stefan Mueller, Ken Korach, Jack-Michel Renoir. Oestrogen receptors pathways to oestrogen responsive elements: The transactivation function-1 acts as the keystone of oestrogen receptor (ER)β-mediated transcriptional repression of ERα. The Journal of Steroid Biochemistry and Molecular Biology, 2007, 104 (3-5), pp.110-122. ⟨10.1016/j.jsbmb.2007.03.002⟩. ⟨inserm-02532933⟩



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