Tamoxifen Resistance in Breast Cancer is Regulated by the EZH2-ERa-GREB1 Transcriptional Axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA400604 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5100704.fastq.gz | Fastqsanger.gz | |||
| SRR5100705.fastq.gz | Fastqsanger.gz | |||
| SRR5100706.fastq.gz | Fastqsanger.gz | |||
| SRR5100707.fastq.gz | Fastqsanger.gz | |||
| SRR5988530.fastq.gz | Fastqsanger.gz |
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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
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-12-01 | GSE103243 | GEO
Project description:Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor ? (ER?) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ER? cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ER? coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671-84. ©2017 AACR.
| S-EPMC5967248 | biostudies-literature
Project description:Identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen in ERa-positive postmenopausal breast tumor patients
2007-10-09 | E-TABM-72 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE41651: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression] GSE41652: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [ChIP-seq] Refer to individual Series
2012-11-15 | E-GEOD-41653 | biostudies-arrayexpress
Project description:Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer. LacZ control vs MMSET overexpression or MMSET DeltaSET overexpression in replicates
2012-11-15 | E-GEOD-41651 | biostudies-arrayexpress
Project description:Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer. Examination of H3K36me2 mark in control and stable EZH2 knockdown cells
2012-11-15 | E-GEOD-41652 | biostudies-arrayexpress
Project description:The cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. Although multiple mechanisms including the tissue-specific coactivators dictate these transcriptional signatures, the feed-forward mechanisms, that evolved to coordinate the cell-type specific transcriptional fulcrums for steroid receptors are not yet identified. In this report, we found that a common feed-forward mechanism between GREB1 and steroid receptors governs the differential effect of GREB1 on steroid hormones in a physiological or pathological context. We found that in physiological (receptive) endometrium, GREB1 is essential for progesterone but not estrogenic responses, whereas in endometriosis, an E2-dependent endometrial pathology, it pre-dominantly mediates estrogenic actions. Specifically, the deletion of GREB1 curtails endometrial receptivity and decidualization, owing to impaired P4-dependent stromal cell proliferation. In contrast, GREB1 is not required for E2-mediated epithelial proliferation of the receptive uterus. Of mechanism, in receptive endometrium, progesterone-induced GREB1 physically interacts with the progesterone receptor on chromatin and functions as a cofactor in a positive feedback mechanism to selectively regulate P4-responses. In pathological conditions (endometriosis), ablation of GREB1 led to the development of smaller endometriotic lesions in mice and reduced E2-driven proliferation of human endometriotic cells. Moreover, E2-induced GREB1 modulated the E2-dependent target gene expression in a feed-forward mechanism. Collectively, acting as a downstream effector, GREB1 governs either P4-responses or E2-responses depending on the physiological or pathological setting. Importantly, this differential action of GREB1 is exerted by a common feed-forward mechanism between GREB1 and steroid receptors, which conceptually advances our understanding of the mechanism(s) that underlie the distinct cell- and tissue-specific actions of steroid hormones.
2024-02-14 | GSE254175 | GEO
Project description:EZH2-GATA6 axis in Pancreatic ductal adenocarcinoma
| PRJNA643152 | ENA
Project description:Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.
2012-11-15 | GSE41651 | GEO