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Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.

Park YY, Kim K, Kim SB, Hennessy BT, Kim SM, Park ES, Lim JY, Li J, Lu Y, Gonzalez-Angulo AM, Jeong W, Mills GB, Safe S, Lee JS - EMBO Mol Med (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

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Related in: MedlinePlus

NR2E3 is highly correlated with ESR1 in breast cancer patientsA. With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 6753 gene features were correlated with that of ESR1 in the NKI breast cancer data set (n = 295). Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of NR2E3 was only positively correlated with ESR1 expression.B. Correlation of ESR1 and NR2E3 expression in UNC breast cancer patient cohort. Scatter plots between ESR1 and NR2E3 in UNC cohort (n = 380).C-D. ESR1-corelated genes (C) or NR2E3 correlated genes (D) in NKI cohort were clustered according to their expression patterns.E. Venn diagram of comparison of two correlated genes in NKI cohort.F-G. ESR1-corelated genes (F) or NR2E3 correlated genes (G) in UNC cohort were clustered according to their expression patterns.H. Venn diagram of comparison of two correlated genes in UNC cohort.
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fig02: NR2E3 is highly correlated with ESR1 in breast cancer patientsA. With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 6753 gene features were correlated with that of ESR1 in the NKI breast cancer data set (n = 295). Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of NR2E3 was only positively correlated with ESR1 expression.B. Correlation of ESR1 and NR2E3 expression in UNC breast cancer patient cohort. Scatter plots between ESR1 and NR2E3 in UNC cohort (n = 380).C-D. ESR1-corelated genes (C) or NR2E3 correlated genes (D) in NKI cohort were clustered according to their expression patterns.E. Venn diagram of comparison of two correlated genes in NKI cohort.F-G. ESR1-corelated genes (F) or NR2E3 correlated genes (G) in UNC cohort were clustered according to their expression patterns.H. Venn diagram of comparison of two correlated genes in UNC cohort.

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.


Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.

Park YY, Kim K, Kim SB, Hennessy BT, Kim SM, Park ES, Lim JY, Li J, Lu Y, Gonzalez-Angulo AM, Jeong W, Mills GB, Safe S, Lee JS - EMBO Mol Med (2011)

NR2E3 is highly correlated with ESR1 in breast cancer patientsA. With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 6753 gene features were correlated with that of ESR1 in the NKI breast cancer data set (n = 295). Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of NR2E3 was only positively correlated with ESR1 expression.B. Correlation of ESR1 and NR2E3 expression in UNC breast cancer patient cohort. Scatter plots between ESR1 and NR2E3 in UNC cohort (n = 380).C-D. ESR1-corelated genes (C) or NR2E3 correlated genes (D) in NKI cohort were clustered according to their expression patterns.E. Venn diagram of comparison of two correlated genes in NKI cohort.F-G. ESR1-corelated genes (F) or NR2E3 correlated genes (G) in UNC cohort were clustered according to their expression patterns.H. Venn diagram of comparison of two correlated genes in UNC cohort.
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fig02: NR2E3 is highly correlated with ESR1 in breast cancer patientsA. With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 6753 gene features were correlated with that of ESR1 in the NKI breast cancer data set (n = 295). Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of NR2E3 was only positively correlated with ESR1 expression.B. Correlation of ESR1 and NR2E3 expression in UNC breast cancer patient cohort. Scatter plots between ESR1 and NR2E3 in UNC cohort (n = 380).C-D. ESR1-corelated genes (C) or NR2E3 correlated genes (D) in NKI cohort were clustered according to their expression patterns.E. Venn diagram of comparison of two correlated genes in NKI cohort.F-G. ESR1-corelated genes (F) or NR2E3 correlated genes (G) in UNC cohort were clustered according to their expression patterns.H. Venn diagram of comparison of two correlated genes in UNC cohort.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

Show MeSH
Related in: MedlinePlus