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 biological and pathological roles of ESR1 have been best characterized in breast cancer, next we performed correlation analysis using gene expression data from breast cancer patients [Netherands Cancer Institute (NKI) data set, n = 295] (van de Vijver et al, 2002). Of the four NRs selected from the NCI-60 cell lines, only the expression of NR2E3 remained significant (r = 0.69, p = 1.59 × 10−9) and correlated positively with the expression of ESR1 in the NKI breast cancer cohort (Fig 2A). A strong correlation with ESR1 was observed in another large breast cancer cohort [University of North Carolina (UNC) cohort, n = 380, r = 0.667, p = 2.2 × 10−16] (Fig 2B; Hu et al, 2006; Oh et al, 2006; Parker et al, 2009). In addition, more than 50% of NR2E3 correlated genes overlapped with those of ESR1 in gene expression data from both the NKI and UNC cohorts (Fig 2C–H). Taken together, the concordant and significant association of NR2E3 with ESR1 in multiple data sets suggests that NR2E3 may be involved in regulation of ESR1-mediated gene expression and pathways in breast cancer.
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.