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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE4006 | GEO | 2006/08/10

SECONDARY ACCESSION(S): PRJNA95225

REPOSITORIES: GEO

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Project description:Estrogen plays an important role in the regulation of vascular tone and in the pathophysiology of cardiovascular disease. Physiological effects of estrogen are mediated through estrogen receptors alpha (ERalpha) and beta (ERbeta), which are both expressed in vascular smooth muscle and endothelial cells. However, the molecular pathways mediating estrogen effects in blood vessels are not well defined. We have performed gene expression profiling in the mouse aorta to identify comprehensive gene sets the expression of which is regulated by long-term (1 wk) estrogen treatment. The ER subtype dependence of the alterations in gene expression was characterized by parallel gene expression profiling experiments in ERalpha-deficient [ERalpha knockout (ERalphaKO)] and ERbeta-deficient (ERbetaKO) mice. Importantly, these data revealed that ERalpha- and ERbeta-dependent pathways regulate distinct and largely nonoverlapping sets of genes. Whereas ERalpha is essential for most of the estrogen-mediated increase in gene expression in wild-type aortas, ERbeta mediates the large majority of estrogen-mediated decreases in gene expression. Biological functions of the estrogen-regulated genes include extracellular matrix synthesis, in addition to electron transport in the mitochondrion and reactive oxygen species pathways. Of note, the estrogen/ERbeta pathway mediates down-regulation of mRNAs for nuclear-encoded subunits in each of the major complexes of the mitochondrial respiratory chain. Several estrogen-regulated genes also encode transcription factors. Overall, these findings provide a foundation for understanding the molecular basis for estrogen effects on vasculature gene expression. Experiment Overall Design: Six estrogen receptor alpha knockout (ERaKO) and six estrogen receptor beta knockout (ERbKO) mice and ten of their wild-type littermates (all female, 2.5-4.5 months of age) were ovarioectomized. Half the mice from each genotype were implanted with 17beta-estradiol pellets, the other half with placebo pellets. After 7-8 days of estrogen/placebo treatment, aortas were harvested, total RNAs were purified for Affymetrix GeneChip microarray analysis, without pooling. This experiment consists of 6 groups with 3 (ERaKO and ERbKO) or 5 (WT) biological replicates per group, for a total of 22 samples.

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

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