Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation

Abstract

Estrogen receptor β (ERβ) and its isoforms have different putative functions and expression patterns in prostate cancer. Current studies on 5′-most exons, 0K and 0N, show that their respective promoters are actively involved in transcription. These data, however, do not explain why ERβ isoforms are differentially expressed in normal and cancerous tissues, since 0K and 0N transcripts are detectable in clinical specimens. Various combinations of 5′ untranslated exons, termed exon 0Xs, associate with promoter 0K only and exon 0Xs accommodate upstream open reading frames (uORFs) reducing protein expression. Moreover, ERβ1, 2, and 5 are transcriptionally linked to promoter 0K; exon 0Xs are spliced only into ERβ2 and ERβ5 transcripts, suggesting that their expressions are regulated post-transcriptionally by exon 0Xs. This study reveals that expression of ERβ1 is regulated primarily at the transcriptional level, whereas that of ERβ2 and ERβ5 is controlled by the interplay between transcriptional and post-transcriptional regulation.

Applicability of Anti-Human Estrogen Receptor β Antibody PPZ0506 for the Immunodetection of Rodent Estrogen Receptor β Proteins

“…The human ERβ gene possesses three promoters. The presence of untranslated internal exons and 5 -untranslated region (5 -UTR) variants inserted near the exons is controversial: Moore et al [19] and Lee et al [10] reported the alternative inclusion of multiple untranslated internal exons (0X1-0X8) between exons 0K and 1, whereas Hirata et al [14] and Smith et al [11,12] did not report their presence. The rat ERβ gene was reported to contain three promoters (E1/P2, 0N/P1, and 0H) [13,15], but no untranslated internal exons have been documented.…”

“…Transcription of ERβ genes is initiated by activation of multiple promoters. Human and rat ERβ genes were reported to possess three promoters (E1, 0N, and 0K in humans, and E1/P2, 0N/P1, and 0H in rats) [10][11][12][13][14][15]. However, few studies have reported on species differences in patterns of alternative ERβ gene promoter usage.…”

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…One other confounding factor occurring in prostate cancer is the expression of the ERb splice variant ERb2. As rodents do not express this splice variant, conclusions about its role in prostate cancer have come from its measurement in prostate cancers (Fujimura et al 2001, Lee et al 2013 and from overexpression in cell lines (Dey et al 2012). So far, there is agreement that the expression of ERb2 in prostate cancer is associated with a poor prognosis (Leung et al 2010).…”

Structural and functional characteristics of oestrogen receptor β splice variants: Implications for the ageing brain

“…Distinct cis ‐regulatory sequences in the human ERβ gene confer a molecular architecture that facilitates alternative splicing in prostate and mammary glands, raising the possibility that these same molecular mechanisms contribute to brain‐region specific splicing. For example, full‐length hERβ transcription can be initiated from two different promoters characterised as 5′ untranslated exons, 0K and 0N, in the prostate and mammary glands . In the prostate gland, hERβ1 and hERβ2 were predominantly transcribed from the 0N promoter, whereas hERβ5 was uniquely transcribed from the 0K promoter .…”

“…[57][58][59] In the prostate gland, hERβ1 and hERβ2 were predominantly transcribed from the 0N promoter, whereas hERβ5 was uniquely transcribed from the 0K promoter. 58 By contrast, both hERβ1 and hERβ5 were transcribed from the 0K promoter in benign and malignant mammary epithelial cells. 60 Depending on the site of transcription initiation, the nascent RNA transcript will include different lengths of 5′ untranslated sequences (UTRa and UTRc), which can have stable secondary structures preventing translation of the RNA product.…”