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
Related in: MedlinePlus
Mentions: We next examined gene networks shared between NR2E3 and ESR1 by comparing gene expression signatures specific to silencing expression of each gene in MCF-7 cells. The Venn diagram (Fig 8A) shows that a substantial number of gene features were identified as downstream targets of both NR2E3 and ESR1, suggesting that a significant part of NR2E3-mediated biological activity is dependent on ESR1. We next tested the clinical relevance of the shared signature by applying a previously established prediction strategy that employs multiple different algorithms (Fig 8B and Method 1 of Supporting Information; Lee et al, 2004, 2006). As expected, the shared gene expression signature was significantly associated with disease recurrence in breast cancer patients (Figs S8 and S9 of Supporting Information) when judged by predicted outcomes of various classifiers. Of interest, the NR2E3-specific gene expression signature (1847 gene features; Gene list on Table 1 of Supporting Information) that was independent of ESR1 was also significantly associated with disease recurrence (Fig 8C), suggesting that NR2E3 activity, that is independent of ESR1 might have important functional roles and prognostic significance in breast cancer. Gene network analysis revealed several interesting features that may contribute to prognostic features of NR2E3 in breast cancer (Fig S10 of Supporting Information).
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.