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ERα and AP-1 coordinate transcription and tamoxifen response in ERα-positive breast cancer

ABSTRACT: ERα and AP-1 coordinate transcription and tamoxifen response in ERα-positive breast cancer

PROVIDER: PRJNA397705 | ENA |

REPOSITORIES: ENA

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			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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c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer [expression profiling]

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

c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer [ChIP-seq]

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

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer

Project description:A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer

| PRJNA774896 | ENA

ERα and AP-1 coordinate transcription and tamoxifen response in ERα-positive breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-03-02 | GSE102412 | GEO

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [ChIP-seq]

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

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [RNA-seq]

2022-10-19 | GSE186644 | GEO

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [GRO-seq]

2022-10-19 | GSE186643 | GEO

Comparative cistromics reveals genomic crosstalk between FOXA1 and ERα in tamoxifen-associated endometrial carcinomas

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

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [GRO-seq]

Project description:A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [GRO-seq]

| PRJNA774902 | ENA

A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [ChIP-seq]

Project description:A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [ChIP-seq]

| PRJNA774903 | ENA