Bulk RNA-seq reveals effects of tamoxifen on endothelial gene expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1038714 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26784009_1.fastq.gz | Fastqsanger.gz | |||
| SRR26784009_2.fastq.gz | Fastqsanger.gz | |||
| SRR26784010_1.fastq.gz | Fastqsanger.gz | |||
| SRR26784010_2.fastq.gz | Fastqsanger.gz | |||
| SRR26784011_1.fastq.gz | Fastqsanger.gz |
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Project description:Transgenic line combination with tamoxifen induction is widely used for biological study. Considering the possibility that tamoxifen induction may alter gene expression, we performed this study to elucidate the potential effect of tamoxifen gavage on the gene expression profile of endothelial cells.
2024-01-25 | GSE247449 | GEO
Project description:Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival but comes with side effects that impact health and quality of life. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating several aspects of the human response. Single cell RNA sequencing reveals that tamoxifen induces widespread gene expression changes in the hypothalamus, particularly in neurons and ependymal cells. These effects are largely dependent on estrogen receptor alpha (ERα), as conditional ERα knockout ablated or reversed tamoxifen-induced changes in gene expression, thermoregulation, bone, and movement. These findings provide mechanistic insights into the effects of tamoxifen on the hypothalamus and suggest that hypothalamic ERα mediates several side effects of tamoxifen therapy.
2021-02-01 | GSE158960 | GEO
Project description:In mouse aorta endothelial cells, populations of endothelial vascular progenitor (EVP) and differentiated (D) cells could be identified by CD31 (lo/hi) and VEGFR2 (lo/hi) expression. These populations were FACS sorted and paired-end bulk RNA-sequencing was performed.
2019-05-27 | E-MTAB-7148 | biostudies-arrayexpress
Project description:Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases, as it acts as an Estrogen Receptor (ER) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol (E2) in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear. Objective: Here we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms. Methods and Results: Using three complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with E2 and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic models mouse targeting either whole ERα in a cell-specific manner or ERα subfunctions (membrane/extra-nuclear versus genomic/transcriptional) demonstrated that E2-induced acceleration of endothelial healing is mediated by membrane ERα in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells. Conclusion: Whereas tamoxifen acts as an anti-estrogen and ERα antagonist in breast cancer, but also on the membrane ERα of endothelial cells, it accelerates endothelial healing through activation of nuclear ERα in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERα.
2023-04-12 | GSE154268 | GEO
Project description:Among pollutants released into the environment by human activities, residues of pharmaceutical agents have been identified worldwide, and are an increasing matter of concern because of their potential impact on ecosystems. Because micro-crustaceans, such as daphnids, are sensitive to chemicals and are key organisms in the food chain, they are particularly convenient for studying the effects of these drugs in the aquatic environment. The aim of this study was to analyse differences of protein expression resulting from acute (2 days) and middle-term (7 days) exposure of Daphnia pulex daphnids to the anticancer drug tamoxifen, with the hope to unveil links between the effects of xenobiotics at the organism level and changes at the molecular level. Using a liquid chromatography - mass spectrometry shotgun approach, about 4000 proteins could be identified with a minimum of one unique peptide, providing the largest proteomics dataset of D. pulex published up to now. Considering both time points and tested concentrations, 189 proteins showed a significant fold change, most of the regulated proteins being observed at the highest concentration tested and for the longer exposure time. About one third of significant proteins were positively regulated, whereas two thirds showed decreased levels after tamoxifen treatment. The identity of regulated proteins suggested a decrease in translation, an increase in protein degradation and changes in carbohydrate and lipid metabolism as the major effects of the drug. Besides these impacted processes, which reflect a general stress response of the organism, some other regulated proteins play a role in Daphnia reproduction. These latter results are in accordance with our previous observations of the impact of tamoxifen on D. pulex reproduction, and illustrate the potential of ecotoxicoproteomics to unravel links between xenobiotic effects at the biochemical and at the organismal level.
2014-10-31 | PXD001257 | Pride
Project description:Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-α-(deoxyguanosin-N2-yl)-tamoxifen (dG-TAM) and (E)-α-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (Pparγ), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD.
2014-10-11 | GSE62267 | GEO
Project description:MERFISH reveals embryonic endothelial heterogeneity
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Project description:Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and hormone receptor positivity. Major challenges in clinical management of ILC is advanced stage at diagnosis, resistance to endocrine therapy, a cornerstone in treating ILC patients, and late recurrence. To elucidate the mechanisms underlying endocrine resistance in ILC, we have generated ILC cell lines (MDA-MB-134-VI and SUM44PE) resistant to tamoxifen, a selective estrogen receptor modulator. Our study reveals methylation mediated silencing of ASS1 and demethylation restored ASS1 expression markedly reducing IC50 for tamoxifen. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired resistance to tamoxifen in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. ASS1 can be a potential biomarker and a therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.
2024-10-18 | MSV000096128 | MassIVE
Project description:Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-M-NM-1-(deoxyguanosin-N2-yl)-tamoxifen (dG-TAM) and (E)-M-NM-1-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (PparM-NM-3), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD. Female and male WSB/EiJ mice were fed diet containing 420 p.p.m. tamoxifen for 12 weeks, and then tamoxifen-DNA adduct formation and gene expression profiles in the livers from four control and four tamoxifen-treated mice were investigated.
2014-10-11 | E-GEOD-62267 | biostudies-arrayexpress
Project description:Resistance to tamoxifen is a major challenge in the treatment of estrogen receptor positive breast cancer. Acquired resistance to drug involves multilayered genetic and epigenetic regulation . The oncogene EZH2 plays significant role in the development of resistance against tamoxifen, widely used in the treatment of breast cancer. Inhibition of EZH2 has proven to reverse the tamoxifen resistance breast cancer cells back to the sensitive state. The molecular mechanism through which EZH2 inhibition triggers its effects are not known.This study was conducted to understand the global change in proteome profile of tamoxifen resistant MCF-7 breast cancer cells as a result of effect of EZH2 knockdown. Label Free Quantitative proteomics revealed a large number of proteins altered in acquired tamoxifen resistant cells compared to the sensitive cells. A total of 286 proteins were identified with normalized RT for each m/z out of which 86 proteins were upregulated by more than 1.3 fold and 98 proteins were down regulated by more than 1.3 fold in MCF-7 tamoxifen resistant breast cancer cells in comparison to the sensitive breast cancer cells. Upon EZH2 knockdown in tamoxifen resistant cells, a total of 115 proteins were found to be altered with 20 proteins upregulated by more than 1.3 fold and 49 proteins down regulated by more than 1.3 fold. Among the top upregulated proteins were L-lactate dehydrogenase A chain, Alpha and Gamma-enolase, Calreticulin, heat shock protein HSP-90-beta, Alpha-actinin-4, Elongation factor 1-alpha, Vimentin, Protein S100A6, Putative protein FAM10A5, Heterogeneous nuclear ribonucleoprotein A1 and Keratin 1. In addition, 15 proteins were found to be down regulated in EZH2si transfected tamoxifen sensitive cells which otherwise were highlyup regulated in resistant cells in the presence of normal level of EZH2. This indicates a possible regulation of these molecules by EZH2 leading to loss of resistance. Our data unveils important molecular players downstream to EZH2 knockdown leading to regain of sensitivity to tamoxifen in acquired tamoxifen resistance.Thus, EZH2 seems to exert its effects through regulation of metabolism, epithelial to mesenchymal transition and protein synthesis & folding. Hence, targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen intamoxifen-resistant cells.
2019-09-30 | PXD012609 | Pride