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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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NR gene network in NCI-60 cell linesOut of 48 human NR genes, expression data of 45 NRs were available in publically available NCI-60 data set and used for hierarchical clustering analysis. The data are presented in matrix format in which rows represent individual gene and columns represent each cell lines. Each cell in the matrix represents the expression level of a gene feature in an individual cancer cell. The red and green colour in cells reflects relative high and low expression levels in log 2 transformed scale.Establishing a Pearson's correlation test p-value of less than 0.001 as indicative of in trans significance with expression patterns of the potential downstream genes, we generated 45 gene sets of in trans correlated genes as putative targets genes for each NR gene; these gene sets were comprised of 86–4580 genes (median = 1275).By cross-comparison of correlated genes in all 45-gene lists, we generated secondary lists reflecting overlap of correlated genes among NR genes. These secondary gene lists are presented in matrix format, and hierarchical clustering analysis was performed with the number of correlated genes overlapped between NR. Heat maps indicate the number of genes overlapped between NRs.Only positively correlated genes are presented (2255 gene features). With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 2255 gene features was positively correlated with that of ESR1. Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of four genes (HNF4A, NR2E3, THRA and PPARA) was significantly correlated with expression of ESR1.
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fig01: NR gene network in NCI-60 cell linesOut of 48 human NR genes, expression data of 45 NRs were available in publically available NCI-60 data set and used for hierarchical clustering analysis. The data are presented in matrix format in which rows represent individual gene and columns represent each cell lines. Each cell in the matrix represents the expression level of a gene feature in an individual cancer cell. The red and green colour in cells reflects relative high and low expression levels in log 2 transformed scale.Establishing a Pearson's correlation test p-value of less than 0.001 as indicative of in trans significance with expression patterns of the potential downstream genes, we generated 45 gene sets of in trans correlated genes as putative targets genes for each NR gene; these gene sets were comprised of 86–4580 genes (median = 1275).By cross-comparison of correlated genes in all 45-gene lists, we generated secondary lists reflecting overlap of correlated genes among NR genes. These secondary gene lists are presented in matrix format, and hierarchical clustering analysis was performed with the number of correlated genes overlapped between NR. Heat maps indicate the number of genes overlapped between NRs.Only positively correlated genes are presented (2255 gene features). With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 2255 gene features was positively correlated with that of ESR1. Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of four genes (HNF4A, NR2E3, THRA and PPARA) was significantly correlated with expression of ESR1.

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).


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)

NR gene network in NCI-60 cell linesOut of 48 human NR genes, expression data of 45 NRs were available in publically available NCI-60 data set and used for hierarchical clustering analysis. The data are presented in matrix format in which rows represent individual gene and columns represent each cell lines. Each cell in the matrix represents the expression level of a gene feature in an individual cancer cell. The red and green colour in cells reflects relative high and low expression levels in log 2 transformed scale.Establishing a Pearson's correlation test p-value of less than 0.001 as indicative of in trans significance with expression patterns of the potential downstream genes, we generated 45 gene sets of in trans correlated genes as putative targets genes for each NR gene; these gene sets were comprised of 86–4580 genes (median = 1275).By cross-comparison of correlated genes in all 45-gene lists, we generated secondary lists reflecting overlap of correlated genes among NR genes. These secondary gene lists are presented in matrix format, and hierarchical clustering analysis was performed with the number of correlated genes overlapped between NR. Heat maps indicate the number of genes overlapped between NRs.Only positively correlated genes are presented (2255 gene features). With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 2255 gene features was positively correlated with that of ESR1. Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of four genes (HNF4A, NR2E3, THRA and PPARA) was significantly correlated with expression of ESR1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376834&req=5

fig01: NR gene network in NCI-60 cell linesOut of 48 human NR genes, expression data of 45 NRs were available in publically available NCI-60 data set and used for hierarchical clustering analysis. The data are presented in matrix format in which rows represent individual gene and columns represent each cell lines. Each cell in the matrix represents the expression level of a gene feature in an individual cancer cell. The red and green colour in cells reflects relative high and low expression levels in log 2 transformed scale.Establishing a Pearson's correlation test p-value of less than 0.001 as indicative of in trans significance with expression patterns of the potential downstream genes, we generated 45 gene sets of in trans correlated genes as putative targets genes for each NR gene; these gene sets were comprised of 86–4580 genes (median = 1275).By cross-comparison of correlated genes in all 45-gene lists, we generated secondary lists reflecting overlap of correlated genes among NR genes. These secondary gene lists are presented in matrix format, and hierarchical clustering analysis was performed with the number of correlated genes overlapped between NR. Heat maps indicate the number of genes overlapped between NRs.Only positively correlated genes are presented (2255 gene features). With a cut-off of Pearson's correlation test p-value of less than 0.001, expression of 2255 gene features was positively correlated with that of ESR1. Of six genes whose correlated genes significantly overlapped with those of ESR1, expression of four genes (HNF4A, NR2E3, THRA and PPARA) was significantly correlated with expression of ESR1.
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).

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