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Estrogens exert numerous actions throughout the human body, targeting healthy tissue while also enhancing the proliferative capacity of breast cancers. Estrogen signaling is mediated by the estrogen receptor (ER), which binds DNA and ultimately affects the expression of adjacent genes. Current understanding of ER-mediated transcriptional regulation is mostly limited to genes whose transcript levels increase following estrogen exposure, though recent studies demonstrate that direct down-regulation of estrogen-responsive genes is also a significant feature of ER action. We hypothesized that differences in cis-regulatory DNA was a factor in determining target gene expression and performed computational and experimental studies to test this hypothesis. From our in silico analyses, we show that the binding motifs for certain transcription factors are enriched in cis-regulatory sequences adjacent to repressed target genes compared to induced target genes, including the motif for RUNX1. In silico analyses were tested experimentally using dual luciferase reporter assays, which indicate that several ER binding sites are estrogen responsive. Mutagenesis of transcription factor motifs (for ER and RUNX1) reduced the response of reporter gene. Further experiments demonstrated that co-recruitment of ER and RUNX1 is necessary for repression of gene expression at some target genes. These findings highlight a novel interaction between ER and RUNX1 and their role in transcriptional repression in breast cancer.

Approximately 70% of breast cancers are estrogen receptor positive, of which 40% have ER mutations. Some of these mutations occur in the three intrinsically disordered regions (IDRs) of estrogen receptor-α (ERα). It is not fully understood how these mutations affect the function of ERα, however they have been suggested to affect DNA and ligand binding, transcriptional activation and dimerization. In this study, we used mammalian one-hybrid (M1H) assays to determine the effect of deletions and mutations in the IDRs on the activation of ERα. We found that deletions in the N- and C-terminal IDRs and 7/11 patient mutations tested decreased the transcriptional activation of ERα in the presence of 17β-estradiol (E2). Interestingly, a 23x glycine-serine replacement of the hinge IDR replacement resulted in a 7-fold increase in activation. Our results show that IDRs are important for full transcriptional activation and regulation of ERα. / 2025-06-23T00:00:00Z

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No description available.