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Interplay between AP-1 and ERalpha in regulating gene expression and proliferation networks in breast cancer cells

ABSTRACT: Estrogen receptor alpha (ERalpha) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERalpha can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that AP-1 is a fundamental factor for ERalpha-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent pro-proliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERalpha can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross-talk between AP-1 and estrogen signaling, we identify a novel ERalpha/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-beta), which is overexpressed in ERalpha-positive breast cancer tissues. Knockdown of PKIB by siRNA results in drastic growth suppression of breast cancer cells. Collectively, our findings support AP-1 as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36586 | GEO | 2012/08/06

SECONDARY ACCESSION(S): PRJNA153755

REPOSITORIES: GEO

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Interplay between AP-1 and ERalpha in regulating gene expression and proliferation networks in breast cancer cells

Project description:Estrogen receptor alpha (ERalpha) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERalpha can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that AP-1 is a fundamental factor for ERalpha-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent pro-proliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERalpha can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross-talk between AP-1 and estrogen signaling, we identify a novel ERalpha/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-beta), which is overexpressed in ERalpha-positive breast cancer tissues. Knockdown of PKIB by siRNA results in drastic growth suppression of breast cancer cells. Collectively, our findings support AP-1 as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs. MCF-7 cells were transfected with a control siRNA or with the pool of siRNAs targeting c-Fos for 72 h and were then treated with vehicle or E2 for 24 h, and global gene expression profiles were assessed. Three or four biological replicates were used for each group.

2012-08-05 | E-GEOD-36586 | biostudies-arrayexpress

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Project description:Two subtypes of the estrogen receptor, ERalpha and ERbeta, mediate the actions of estrogens, and the majority of human breast tumors contain both ERalpha and ERbeta. To examine the possible interactions and modulatory effects of ERbeta on ERalpha activity, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing ERbeta, along with their endogenous ERalpha. We have examined the effects of ERÎ² expression on genome-wide gene expression by Affymetrix GeneChip microarrays. We find that ERbeta modulated estrogen gene expression on nearly 24% of E2-stimulated genes but only 8% of E2-inhibited genes. We find that ERbeta modulation is gene-specific, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Introduction of ERbeta into ERalpha-containing cells induced up/down-regulation of many estrogen target in the absence of any added ligand. In addition, ERbeta presence elicited the expression of a unique set of genes that were not regulated by ERalpha alone. ERbeta modulated the expression of genes in many functional categories, but the greatest numbers were associated with transcription factor and signal transduction pathways. Regulation of multiple components in the TGF beta, SDF1, and semaphorin pathways, may contribute to the suppression of proliferation observed with ERbeta both in the presence and absence of estrogen. Hence, ERbeta modulates ERalpha gene regulation in diverse ways that may contribute to its growth-inhibiting beneficial effects in breast cancer Experiment Overall Design: MCF-7 cells expressing endogenous ERalpha were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 5 or 50. Cells were infected with adenovirus for a period of 48hr before treatment with ligand (vehicle control or 10nM 17beta-estradiol) for a additional period of 24hr before harvest.

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Mufudza2012 - Estrogen effect on the dynamics of breast cancer

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Cellular reprogramming by the conjoint action of ERalpha, FOXA1 and GATA3 to a ligand-inducible growth state

Project description:Despite the role of the estrogen receptor alpha (ERalpha) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ERalpha into ERalpha-negative cells paradoxically has been growth inhibition. We map the binding profiles of ERalpha and its interacting transcription factors (TFs), FOXA1 and GATA3, in MCF-7 breast carcinoma cells. We observe that these three TFs form a functional enhanceosome and cooperatively modulate the transcriptional networks previously ascribed to ERalpha alone. We demonstrate that these enhanceosome-occupied sites are associated with optimal enhancer characteristics with highest p300 coactivator recruitment, RNA Pol II occupancy, and chromatin opening. The enhancesome binding sites appear to regulate the genes driving core ERalpha function. Most importantly, we show that transfection of all three TFs was necessary to reprogram the ERalpha-negative MDA-MB-231 and BT-459 cells to restore the estrogen responsive growth and to transcriptionally resemble the estrogen-treated ERalpha-positive MCF-7 cells. Cumulatively, these results suggest that all of the enhanceosome components comprising ERalpha, FOXA1 and GATA3 are necessary for the full repertoire of the cancer-associated effects of the ERalpha.

2011-09-05 | GSE29073 | GEO

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