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 ESR1 is known to be an important prognostic marker in breast cancer management (Fisher et al, 1988; Hilsenbeck et al, 1998; Loi et al, 2008; Oh et al, 2006), we tested whether NR2E3 (an upstream regulator of ESR1) is also significantly associated with prognosis in breast cancer patients. For our analysis, we used a public database (Gene Expression Omnibus in the National Center for Biotechnology Information) to retrieve gene expression data of breast cancer patients. Patients in the NKI cohort (n = 295; van de Vijver et al, 2002) were first dichotomized according to expression levels of ESR1. As expected, two groups of breast cancer patients showed a significant difference in recurrence-free survival (RFS; Fig 6A). When the patients were dichotomized according to expression level of NR2E3, RFSs of patients with higher expression of NR2E3 were significantly better than that of those with lower expression of NR2E3 (Fig 6B). Furthermore, patients with a higher expression of both ESR1 and NR2E3 had the best clinical outcomes, while patients with a lower expression of both ESR1 and NR2E3 had the worst clinical outcomes (Fig 6C). The association of NR2E3 expression with prognosis also remained significant in a large independent breast cancer cohort (UNC cohort, n = 380; Hu et al, 2006; Oh et al, 2006; Parker et al, 2009; Fig 6D–F).
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.