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: Since little is known about the function of NR2E3 in breast cancer, we investigated possible roles of NR2E3 related to the ESR1-signalling pathway using NR2E3-specific small hairpin RNA (shRNA) in estrogen receptor (ER)-positive breast cancer MCF-7 cells (Fig 3A). Surprisingly, when expression of NR2E3 was silenced by shRNA, expression of ESR1 and its downstream targets (GATA3, PGR, CCND1 and TFF1) were also significantly downregulated (Fig 3B); reduced expression of ESR1 and its downstream targets was also validated at the protein level (Fig 3E). The effect of silencing NR2E3 expression on ESR1 and its downstream targets was also highly reproducible in another ER-positive breast cancer cell line: T47D (Fig 3C and D). It is interesting to point out that expression of FOXA1 was not altered after silencing NR2E3expression in MCF-7 cells while its expression was down-regulated in T47D cells, suggesting that additional regulatory mechanisms for expression of FOXA1 might exist in MCF-7 cells. Transcriptional activity of ESR1 was also diminished by small hairpin NR2E3 (shNR2E3; Fig 3F). Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.