Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.
Bottom Line: By applying systems-level re-analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1.Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and a favourable response to tamoxifen treatment in women with ER-positive breast cancer.Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 and the clinical relevance of NR2E3 in breast cancer.
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.Show MeSH
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Mentions: Many biochemical and genetic studies have demonstrated that coregulators are critically important for the function of NRs and the induction of NR-dependent genes (Xu et al, 2009). Since NR coactivators (NCOAs, also known as steroid receptor coactivators) are the best-known coregulators of NRs and interact with diverse NRs in human cancer (Xu et al, 2009), we first investigated their possible role in regulating ESR1 expression by NR2E3. After silencing NCOA1, 2 and 3 by their specific siRNA (SMART Pool) in MCF-7 cells, we measured gene expression of ESR1 and its downstream target genes. While silencing the expression of the NCOA family genes significantly downregulated expression of ESR1 downstream target genes, expression of ESR1 itself was not altered (Fig 5A and B). When we used different siRNAs to knock down NCOA family members, the result were significant as shown in Fig S2B and C of Supporting Information. This suggests that the NCOAs are only involved in regulation of ESR1's transcriptional activity and do not influence NR2E3-mediated regulation of ESR1 expression in breast cancer cells.
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.