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: To uncover potential interacting network of NR genes and to generate testable hypotheses, we have used publicly available gene expression data from NCI-60 cell lines that have been used extensively as an exploration data set (Amundson et al, 2008; Hsu et al, 2009; Park et al, 2010; Potti et al, 2006; Reinhold et al, 2010; Wang & Li, 2009). We first tried to uncover an NR network using direct correlation of expression patterns of NRs across NCI-60 cell lines but were not able to produce a recognizable network with a higher degree of interaction among NRs (Fig 1A). Since all NRs are transcription factors that regulate expression of many genes, we hypothesized that expression patterns of direct or indirect target genes regulated by NRs would be well correlated with patterns of NR expression. Therefore, we identified genes whose expression was significantly correlated with those of NR genes in NCI-60 cell lines as potential downstream targets of NRs. After establishing a Pearson's correlation test p-value of less than 0.001 as being indicative of significance with expression patterns of the NR genes, we generated correlated gene lists of 45 NRs (Fig 1B). As expected, many of the identified correlated genes were previously identified as downstream targets of NR genes. For example, expression of GATA3, a well-known downstream target of ESR1 (Eeckhoute et al, 2007), was highly correlated with expression of ESR1 (r = 0.76, p = 3.09 × 10−12).
Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.