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A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer.

Shen C, Huang Y, Liu Y, Wang G, Zhao Y, Wang Z, Teng M, Wang Y, Flockhart DA, Skaar TC, Yan P, Nephew KP, Huang TH, Li L - BMC Syst Biol (2011)

Bottom Line: Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression.The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Computational Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

ABSTRACT

Background: Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood.

Results: We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERα target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERα regulatory network was unresponsive to 17β-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.

Conclusions: We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

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Effect of selective ERα modulators. (A) The agonistic effect of 4-OH tamoxifen is greater on genomic mechanism than on antagonistic or partial effects (p = 0.01). (B) No evidence for agonistic, antagonistic, or partial effects of endoxifen on genomic or non-genomics mechanisms.
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Figure 4: Effect of selective ERα modulators. (A) The agonistic effect of 4-OH tamoxifen is greater on genomic mechanism than on antagonistic or partial effects (p = 0.01). (B) No evidence for agonistic, antagonistic, or partial effects of endoxifen on genomic or non-genomics mechanisms.

Mentions: We further classified the effects of OHT and endoxifen on ERα genomic/non-genomic and up/down regulation. There was a tendency for a greater agonistic effect on ERα genomic targets than non-genomic targets after E2 or OHT treatment (p = 0.01; Figure 4A). However, this difference in agonistic activity on genomic/non-genomic targets was not seen (p = 0.67, Figure 4B) after E2 or endoxifen treatment.


A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer.

Shen C, Huang Y, Liu Y, Wang G, Zhao Y, Wang Z, Teng M, Wang Y, Flockhart DA, Skaar TC, Yan P, Nephew KP, Huang TH, Li L - BMC Syst Biol (2011)

Effect of selective ERα modulators. (A) The agonistic effect of 4-OH tamoxifen is greater on genomic mechanism than on antagonistic or partial effects (p = 0.01). (B) No evidence for agonistic, antagonistic, or partial effects of endoxifen on genomic or non-genomics mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117732&req=5

Figure 4: Effect of selective ERα modulators. (A) The agonistic effect of 4-OH tamoxifen is greater on genomic mechanism than on antagonistic or partial effects (p = 0.01). (B) No evidence for agonistic, antagonistic, or partial effects of endoxifen on genomic or non-genomics mechanisms.
Mentions: We further classified the effects of OHT and endoxifen on ERα genomic/non-genomic and up/down regulation. There was a tendency for a greater agonistic effect on ERα genomic targets than non-genomic targets after E2 or OHT treatment (p = 0.01; Figure 4A). However, this difference in agonistic activity on genomic/non-genomic targets was not seen (p = 0.67, Figure 4B) after E2 or endoxifen treatment.

Bottom Line: Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression.The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Computational Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

ABSTRACT

Background: Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood.

Results: We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERα target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERα regulatory network was unresponsive to 17β-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.

Conclusions: We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

Show MeSH
Related in: MedlinePlus