Expression of estrogen receptor β isoforms is regulated by transcriptional and post-transcriptional mechanisms
Résumé
Although estrogen receptors (ERs) mediate breast tumour behaviour, the precise role of ERβ remains unclear. This is mainly because analyses have been complicated by the presence in breast tissue of three ERβ protein variants (ERβ1, 2 and 5) that derive from differential 3' splicing. We have recently identified the first known mechanisms responsible for the differential control of isoform expression, involving regulation of translation via 5' untranslated regions (UTRs). In this study, we have uncovered further complexity involving the influence of multiple promoters and cross-talk between 5' and 3'UTRs. We demonstrate that full-length ERβ messages are transcribed from three separate promoters; two promoters are well-established within the literature while the third represents a novel finding. Each promoter produces transcripts with distinct 5'UTRs. The differential 3' splicing that produces transcripts coding for the ERβ isoforms also defines isoform-specific 3'UTRs. We identified exact 3'UTR sequences for each isoform, and show that alternative polyadenylation sites are used in a cell-type specific manner to produce transcripts with 3'UTRs of different lengths. Critically, we show that 5' and 3'UTRs combine to specify the efficiencies with which individual transcripts are translated, with 3'UTR length having a key influence. In addition, we demonstrate how 17β-estradiol, a key driver of breast cancer development, impacts on the regulation of ERβ expression at both transcriptional and translational levels.
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