Identification of novel transcript variants of estrogen receptor α, β and progesterone receptor gene in human endometrium

Abstract

The human progesterone receptor (PR) and estrogen receptor genes (ESR1 and ESR2) are known to code for a multitude of transcript variants resulting from alternative splicing. Many of them are translated into nuclear receptor proteins with altered structure and function. Expression of these alternative estrogen and progesterone receptors modulates the cellular response to sexual steroid hormones. Recent studies also suggested their significance in development of hormone-dependent diseases like gynecological cancers. We report identification of 12 new transcript variations of the PR, ESR1, and ESR2 gene in human endometrium which result from differential exon-skipping. We succeeded in cloning of four new double or triple exon-deletion transcript variants of ERα, four single, double or triple exon-skipped mRNA isoforms of ERβ, and four new transcript variations of PR gene. Sequence analysis suggested that at least four of them, ERαΔ5/6, ERαΔ5/6/7, PRΔ7, and PRΔ6/7 are translated into receptor proteins which might exert ligand-independent effects on steroid hormone signalling. Comparison of pre- and post-menopausal endometrium revealed differential expression of PRΔ6/7, ERαΔ5/6/7, ERαΔ3/4/5, and ERβΔ1-0N. We also report differential expression of the exon-skipped isoforms in a panel of human cancer cell lines derived from the breast, ovary, and endometrium. Our identification of additional transcript variations further increases the complexity of steroid hormone receptor gene expression and signalling.

Role of estrogen receptor β in gynecological cancer

“…Given that expression of ERβ has been reported to decline during tumorigenesis of breast, colon and prostate cancer, this receptor has been proposed to act as a tumor-suppressor [9][10][11][12][13]. In the last years, several studies including those from our lab examining the role of ERβ in gynecological cancer have been published suggesting that this receptor might play differential roles in ovarian and endometrial cancer [14][15][16][17].…”

Structure, tissue distribution and estrogen regulation of splice variants of the sea bream estrogen receptor α gene

“…Perlman et al, 2005;Nott et al, 2008;Springwald et al, 2010). These transcripts may result from multiple mechanisms, the most common being alternative promoter usage and alternative mRNA splicing with deletion of one or more exons (Tiffoche et al, 2001;Hirata et al, 2003;Perlman et al, 2005;Ishunina and Swaab, 2008;Nott et al, 2008).…”

PGR (progesterone receptor)

“…These are a result of the deletion of some of the eight exons of PR or by the retention of intronic sequences (see Cork et al 2008). Two variants were translated into protein and were found to be differentially expressed in the endometrium (Springwald et al 2010). However, the functional status of the variants is unclear.…”