Epigenetic and Expression Profiling of Tissue Selective Estrogen Compounds in Breast Epithelial Cell Lines
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA397790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5922480.fastq.gz | Fastqsanger.gz | |||
| SRR5922490.fastq.gz | Fastqsanger.gz | |||
| SRR5922500.fastq.gz | Fastqsanger.gz | |||
| SRR5922510.fastq.gz | Fastqsanger.gz | |||
| SRR5922520.fastq.gz | Fastqsanger.gz |
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Project description:Current approaches to menopausal hormone therapy consist of compounds which provide tissue specific beneficial effects while working to minimize any increase in cancer risk associated with replacement therapy. In this study, an examination of the genomic distribution of histone modification and expression changes in two breast epithelial cell lines, the normal MCF10A cell line and the MCF-7 breast cancer cell line, upon treatment with several of the current therapies used for treating post-menopausal symptoms is presented. Analysis of the observed changes upon treatment with either 17-estradiol (E2), a combined treatment with the top 10 most abundant Premarin chemical equivalents (EC10), the non-steroidal SERM, Bazadoxifene (BZA) and the TSEC; BZA combined with EC10 (Duavee) or BZA combined with E2 provides evidence of expression changes in genes involved in DNA replication, nucleosome assembly, RNA-splicing and processing, biological regulation and cell signaling, and many of the known steroid response genes. There were distinct global changes in chromatin states observed that were specific to each of the breast epithelial cell type normal, basal MCF10A and ESR/PGR positive luminal breast cancer MCF7 cell lines and selective changes observed upon treatment with each of the treatment groups. Specifically, we observed a global loss of H3K4ac upon treatment with BZA. These changes were observed in both ESR1 bound and non-bound regions suggesting modifications in both promoters and enhancer regions. The levels of H3K4ac upon treatment of BZA showed a decrease below basal non-treated H3K4ac levels in MCF7. There was an increase observed with E2 and EC10 treatment in MCF7 that was mitigated by the addition of BZA to either steroid as a combined treatment. This study provides a better understanding of the role of epigenetic modifications in endocrine responsiveness and provides evidence of an improved therapeutic profile for combined TSEC compounds for treating and managing the overall physiological effects of declining estrogen.
2020-08-01 | GSE102469 | GEO
Project description:Current approaches to menopausal hormone therapy consist of compounds which provide tissue specific beneficial effects while working to minimize any increase in cancer risk associated with replacement therapy. In this study, an examination of the genomic distribution of histone modification and expression changes in two breast epithelial cell lines, the normal MCF10A cell line and the MCF-7 breast cancer cell line, upon treatment with several of the current therapies used for treating post-menopausal symptoms is presented. Analysis of the observed changes upon treatment with either 17-estradiol (E2), a combined treatment with the top 10 most abundant Premarin chemical equivalents (EC10), the non-steroidal SERM, Bazadoxifene (BZA) and the TSEC; BZA combined with EC10 (Duavee) or BZA combined with E2 provides evidence of expression changes in genes involved in DNA replication, nucleosome assembly, RNA-splicing and processing, biological regulation and cell signaling, and many of the known steroid response genes. There were distinct global changes in chromatin states observed that were specific to each of the breast epithelial cell type normal, basal MCF10A and ESR/PGR positive luminal breast cancer MCF7 cell lines and selective changes observed upon treatment with each of the treatment groups. Specifically, we observed a global loss of H3K4ac upon treatment with BZA. These changes were observed in both ESR1 bound and non-bound regions suggesting modifications in both promoters and enhancer regions. The levels of H3K4ac upon treatment of BZA showed a decrease below basal non-treated H3K4ac levels in MCF7. There was an increase observed with E2 and EC10 treatment in MCF7 that was mitigated by the addition of BZA to either steroid as a combined treatment. This study provides a better understanding of the role of epigenetic modifications in endocrine responsiveness and provides evidence of an improved therapeutic profile for combined TSEC compounds for treating and managing the overall physiological effects of declining estrogen.
2020-08-01 | GSE102436 | GEO
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2020-08-01 | GSE102472 | GEO
Project description:In addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ERbeta is a more desirable therapeutic target because ERalpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERbeta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ERbeta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ERbeta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ERbeta or ERalpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ERbeta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERbeta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERbeta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERbeta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERbeta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders. Keywords: estrogen receptor, gene regulation, TNF
2008-04-12 | GSE11115 | GEO
Project description:This study was designed to determine the effects of plant derived compounds on the transcriptome of estrogen receptor positive breast cancer. Phytoestrogens are compounds produced by plants that possess weak estrogenic activity. They can be found in a wide variety of plants, including fruits and vegetables, but are most abundant in leguminous plants. Legumes are consumed in almost every diet throughout the world, and in addition to the seeds, many other parts of the plant are also edible, including the pods of some varieties. Soybeans have been demonstrated to contain high concentrations of the isoflavones daidzein and genistein, which are re-sponsible for many of the health benefits of soy. Besides isoflavonoids, flavonoids also exert estrogenic activity, but usually at a much lower level of activity compared to that of isoflavonoids. Also, some flavonoids, including kaempferol and quercetin, canexhibit antiestrogenic activity, with several legumes being a source of these flavo-noids. Coumestrol, a coumestan with high estrogenic activity in cell and animal as-says, is also present in several legume seeds and sprouts. These underutilized plant compounds could hold previously unknown potential for antioxidant activity, anti-inflammation activity, cholesterol lowering ability, and even anticancer activity. The goal of the present study was to identify the effects of plant derived compounds on estrogen receptor positive cell line to determine if the compound possess estrogenic or anti-estrogenic activity, thereby highlighting potential implications on human health through diet.
2024-09-30 | GSE277758 | GEO
Project description:Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase (HPRT), suggesting an elevated gene-dosage of HPRT in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-Diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy.
2015-10-03 | GSE73710 | GEO
Project description:Selective estrogen receptor modulators (SERMs), including the SERM/SERD bazedoxifene (BZA), are used to treat postmenopausal osteoporosis and may reduce breast cancer (BCa) risk. One of the most persistent unresolved questions regarding menopausal hormone therapy is compromised control of proliferation and phenotype because of short- or long-term administration of mixed-function estrogen receptor (ER) ligands. To gain insight into epigenetic effectors of the transcriptomes of hormone and BZA-treated BCa cells, we evaluated a panel of histone modifications. The impact of short-term hormone treatment and BZA on gene expression and genome-wide epigenetic profiles was examined in ERαneg mammary epithelial cells (MCF10A) and ERα+ luminal breast cancer cells (MCF7). We tested individual components and combinations of 17β-estradiol (E2), estrogen compounds (EC10) and BZA. RNA-seq for gene expression and ChIP-seq for active (H3K4me3, H3K4ac, H3K27ac) and repressive (H3K27me3) histone modifications were performed. Our results show that the combination of BZA with E2 or EC10 reduces estrogen-mediated patterns of histone modifications and gene expression in MCF-7ERα+ cells. In contrast, BZA has minimal effects on these parameters in MCF10A mammary epithelial cells. BZA-induced changes in histone modifications in MCF7 cells are characterized by altered H3K4ac patterns, with changes at distal enhancers of ERα-target genes and at promoters of non-ERα bound proliferation-related genes. Notably, the ERα target gene GREB1 is the most sensitive to BZA treatment. Our findings provide direct mechanistic-based evidence that BZA induces epigenetic changes in E2 and EC10 mediated control of ERα regulatory programs to target distinctive proliferation gene pathways that restrain the potential for breast cancer development.
| S-EPMC9302754 | biostudies-literature
Project description:In addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ERbeta is a more desirable therapeutic target because ERalpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERbeta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ERbeta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ERbeta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ERbeta or ERalpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ERbeta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERbeta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERbeta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERbeta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERbeta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders. Experiment Overall Design: Expression of ER in the U2OS-ERÃ cells was induced with doxycycline. The cells were treated in the absence or presence of 10 nM E2 for 18 h followed by incubation with TNF-{alpha} for 1 h. Total RNA were extracted, followed by cRNA labelling, and hybridization of fragmented samples to the U95Av2 arrays (n = 3 for untreated, n = 4 for TNF-{alpha}-treated, n = 4 for TNF-{alpha}- and E2-treated samples). The data were analyzed using the Microarray Suite Version 5.0 with the default parameters. The comparative data generated for each treated group were analyzed further in Microsoft Excel. TNF-{alpha}-induced genes were selected for further analysis only if they had a 1.2 signal log ratio mean value (2.3-fold change) and were statistically significant (p < 0.05) in at least three separate experiments.
2008-06-11 | E-GEOD-11115 | biostudies-arrayexpress
Project description:Effets of plant compounds on estrogen receptor positive breast cancer cell line MCF-7
| PRJNA1163890 | ENA
Project description:In this study, we investigated the potential estrogenicity of soy protein isolate (SPI) as opposed to pure isoflavones (i.e., estradiol) in the prepubertal stage of testis development. Bioinformatics analysis of the microarray analysis indicate that rather than acting as a weak estrogen in the developing testis, SPI appears to act as a selective estrogen receptor modulator with little effect on reproductive processes.
2017-02-02 | GSE94392 | GEO