ERα and AP-1 coordinate transcription and tamoxifen response in ERα-positive breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA397705 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5919370.fastq.gz | Fastqsanger.gz | |||
| SRR5919364.fastq.gz | Fastqsanger.gz | |||
| SRR5919365.fastq.gz | Fastqsanger.gz | |||
| SRR5919366.fastq.gz | Fastqsanger.gz | |||
| SRR5919367.fastq.gz | Fastqsanger.gz |
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Project description:A critical mechanism that has been proposed for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and that c-Jun chromatin binding shows extensive overlap with ER binding at the global level. Further, we show that c-Jun overexpression reprograms ER chromatin binding and modulates ER-mediated gene regulation. Our data are consistent with a mechanism where estrogen/ER-dependent crosstalk with AP-1 at the transcriptional level is mediated through the tethering of ER to DNA bound AP-1. Additionally, in our system c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated cistrome, transcriptome, and clinical data reveal TGFBI as a candidate gene which may confer tamoxifen resistance by ER and AP-1 crosstalk. Further, we show that TGFBI expression is elevated in breast cancer compared to normal breast. Together, our data provide a novel genome-wide footprint of ER and AP-1 crosstalk and suggest AP-1 and TGFBI signaling as potential therapeutic targets in AP-1-overexpressing ER-positive breast tumors.
2018-03-02 | GSE102367 | GEO
Project description:A critical mechanism for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and is recruited globally to ER binding regions. Interestingly, we identify differential motif enrichment between unique ER binding regions and unique c-Jun binding regions, with FoxA1 motif enriched in both sets of binding regions, whereas GATA3 motif only specifically enriched in the unique ER binding regions but not in the unique Jun binding regions. We demonstrate that the primary mechanism for estrogen/ER-dependent transcriptional responses is the tethering of ER to DNA under conditions where it cooperates with AP-1. We provide evidence that c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated omics data reveal TGFBI as one of the most perturbed genes regulated by c-Jun. TGFBI knockdown suppresses the growth of breast cancer cells and is critical for increasing the sensitivity of tamoxifen-resistant cells to tamoxifen. We show that TGFBI expression is elevated in breast cancer than in normal breast and the basal-like tumors express high levels of TGFBI. TGFBI expression is associated with poor patient survival in ER+ breast cancer receiving endocrine therapy, highlighting a role of AP-1 via TGFBI signaling as a major determinant of endocrine response in ER+ breast tumor.
2018-03-02 | GSE102410 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-03-02 | GSE102412 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186644 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186643 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186645 | GEO
Project description:Tamoxifen, which is used to treat breast cancer, increases the risks of endometrial cancer. In this study, we performed a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. Our results define conserved sites for genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer.
2016-06-07 | GSE81213 | GEO
Project description:Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer.
2020-06-01 | GSE95302 | GEO
Project description:In this study, we probed the importance of OGT activity for the survival of Tamoxifen-sensitive (TamS) and Tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over half of all breast cancers, and the defining characteristic of the ERα-positive disease. ERα-positive breast cancers are successfully treated with Tamoxifen; however, a significant number of patients develops Tamoxifen-resistant disease. We show here that in vitro development of Tamoxifen-resistance results in acquired sensitivity to OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by undergoing significant chromatin compaction. In the TamR cells, however, OGT inhibition induces ERRFI1 tumor-suppressor gene expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, while activation of the ERBB-signaling is one of the best understood mechanism for Tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2, and provide data to support that this occurs through promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p=9.2e-8). In summary, we show that Tamoxifen-resistance is associated with acquired sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.
2020-10-22 | GSE148186 | GEO
Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress