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Gene Expression Preferentially Regulated by Tamoxifen in Breast Cancer Cells

ABSTRACT: The beneficial effect of the selective estrogen receptor modulator (SERM) tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here we report that in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of more than 60 genes in estrogen receptor alpha (ERa)-positive MCF-7 human breast cancer cells which are minimally regulated by estradiol or raloxifene. This gene regulation by tamoxifen is mediated by ERa and is reversed by estradiol or ICI 182,780. We find that the introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes, suggesting that ERbeta is capable of repressing certain actions of tamoxifen. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, the expression level of these genes was examined in breast tumors of women who had received treatment with tamoxifen. High expression of two of the tamoxifen stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive tumors, and hence appear to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen-preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. Keywords: ligand response in two ER backgrounds

ORGANISM(S): Homo sapiens

PROVIDER: GSE4025 | GEO | 2006/07/28

SECONDARY ACCESSION(S): PRJNA95129

REPOSITORIES: GEO

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Transcription profiling of human MCF-7 breast cancer cell line transfected with adenovirus expressing Erbeta treated with estrogen or tamoxifen reveals tamoxifen can selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene.

Project description:The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERalpha and reversed by E2 or ICI 182,780. Introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy.

2007-10-02 | E-GEOD-4025 | biostudies-arrayexpress

Estrogen effects on MCF-7 breast cancer cells co-expressing ERa and ERb

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 ERβ 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 Keywords: modulatory effects of ERb on ERa

2006-08-10 | GSE4006 | GEO

Transcription profiling of human cancer cell line MCF-7 - estrogen effects where MCF7 is co-expressing ERa and ERb

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.

2009-04-24 | E-GEOD-4006 | biostudies-arrayexpress

Estrogen-responsive Estrogen Receptor alpha binding sites in MCF-7 by ChIP-seq

Project description:Identification of Estrogen Receptor alpha (ERa) binding sites by ChIP-seq in MCF-7 breast cancer cells following an estrogen treatment. This study describes molecular effects of estradiol treatment and subsequent regulation by ER for a single gene/locus. A public ER chipseq (available in SRA as ERR011973), in addition to our own data, guided us to regulatory regions were ER was binding that were then analyzed in detail using "manual" ChIP. MCF-7 cells were treated for 1 h either 10 nm estradiol (E2) or vehicle (ethanol) and subjected to ChIP using antibodies against ERa or IgG.

2012-12-17 | E-GEOD-34759 | biostudies-arrayexpress

Tamoxifen treatment of MCF-7 breast cancer cells

Project description:Tamoxifen is an anti-estrogen drug used in the treatment of Estrogen Receptor (ER) positive breast cancer. Effects and side effects of tamoxifen is the sum of tamoxifen and all its metabolites. Using concentrations that mimic the clinical situation we examined effects of 4OHtam, 4OHNDtam and NDtam on global gene expression in 17beta-estradiol (E2) treated MCF-7 cells.

2014-10-24 | E-MTAB-2729 | biostudies-arrayexpress

Transcription profiling of human breast cancer cells (MCF-7) coexpressing ERalpha and Erbeta, treated with phytoestrogens

Project description:We used microarrays to detail the global transcriptional response mediated by ERalpha or ERbeta to the phytoestrogen genistein in the MCF-7 human breast cancer cell model. Experiment Overall Design: MCF-7 human breast cancer cells expressing endogenouse Estrogen Receptor Alpha (ERalpha) were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 20. Cells were then treated with either vehicle control (veh), 6nM 17beta-estradiol (E2), 6nM genistein (LG), 300nM genistein (HG), 300nM S-Equol (EQ), HG+3uM ICI182,780 (IG), EQ+3uM ICI 182,780(IE) for a additional periods of 4h or 24hr before RNA extraction and hybridization on Affymetrix microarrays. We sought to determine if genistein and S-Equol, phytoestrogens selective for the ERbeta can elicit transcriptional response distinctive from those mediated by the ERalpha.

2008-04-10 | E-GEOD-9936 | biostudies-arrayexpress

Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma

Project description:Purpose: Endocrine therapies, such as tamoxifen are commonly given to most patients with estrogen receptor (ER) alpha-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5-10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen. Experimental Design: We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with two years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors. Results: ERbeta was associated with increased survival (distant disease-free survival, P=0.01; overall survival, P=0.22), and in particular within ERalpha-negative patients (P=0.003; P=0.04), but not in the ERalpha-positive subgroup (P=0.49; P=0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% CI, 1.8-106; P=0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% CI, 0.21-0.89; P=0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature. Conclusion: Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients, and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the U.S. alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen. Keywords: Disease state analysis

2007-04-01 | GSE6577 | GEO

Transcription profiling of human estrogen receptor positive MCF7 cells stably transfected with aromatase gene treated with testosterone, 17 B-estradiol, two aromatase inhibitors (letrozole and anastrozole), and an anti-estrogen (tamoxifen)

Project description:Anti-estrogens and aromatase inhibitors are important drugs in the treatment of estrogen-dependent breast cancer. In order to investigate the effects of these drugs on gene expression in breast cancer cells, we treated estrogen receptor-positive MCF-7 cells, stably transfected with the aromatase gene (known as MCF-7aro cells), with testosterone, 17Î²-estradiol, two aromatase inhibitors (letrozole and anastrozole), and an anti-estrogen (tamoxifen). Microarray analyses using Affymetrix Human Genome U133A GeneChips were carried out using total RNA isolated from the control and treated cells. When comparing the effect of each inhibitor on gene expression we observe that letrozole and anastrozole are more similar in terms of the genes they affect, compared to treatment with tamoxifen. The results of this study provide us with a better understanding of the actions of both aromatase inhibitors and anti-estrogens at the molecular level. We believe that the results of this study serve as the first step in identifying unique expression patterns following drug treatment, and that this will ultimately be useful in customizing patient treatment strategies for estrogen-dependent breast cancer. The data presented here have been processed using the R-Project Bioconductor statistical tools package using the affy library. The following were applied: RMA background correction, pmonly probe-level correction, quantile normalization, avgdiff summary method. Raw data is provided in the form of .CEL files.

2007-10-27 | E-GEOD-2225 | biostudies-arrayexpress

Profiling of ER+ BrC cells with and without estradiol in both cell cultures and xenografts

Project description:We generated DNA microarray based gene expression profiles from three estrogen receptor a (ERa) positive breast cancer cell lines stimulated by 17ß-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. Keywords: Cell line and xenograft comparisons

2006-03-03 | GSE3834 | GEO

Estrogen-responsive Estrogen Receptor alpha binding sites in MCF-7 by ChIP-seq

2012-12-17 | GSE34759 | GEO

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