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 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 α (ERα) 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 ERα 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 ERα 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:This SuperSeries is composed of the SubSeries listed below.
2017-12-01 | GSE103243 | GEO
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: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: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
2006-07-28 | GSE4025 | GEO
Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270769 | GEO
Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270163 | GEO
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:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Experiment Overall Design: Wild type and osteoclast-specific Estrogen Receptor alpha knock-out mice were ovariectomized. The number of both genotypes of mice was eight. The mice of each genotypes were divided to vehicle control and estrogen treated group. Four hours after chemical treatment, the distal 5 mm of the left femurs were harvested after sacrificing by cervical dislocation and total RNAs were purified for Affymetix GeneChip microarray analysis without pooling. Therefore, this experiment consists of four groups with four replicates per group.
2008-06-15 | E-GEOD-7798 | biostudies-arrayexpress
Project description:Immunoaffinity enrichemt of GREB1 to co-enrich HSP90
2018-05-02 | PXD008631 | Pride