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

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

PROVIDER: PRJNA774902 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16587620.fastq.gz	Fastqsanger.gz
	SRR16587621.fastq.gz	Fastqsanger.gz
	SRR16587622.fastq.gz	Fastqsanger.gz
	SRR16587623.fastq.gz	Fastqsanger.gz

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A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [GRO-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 | GSE186643 | GEO

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

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

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

| PRJNA774896 | ENA

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

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

| PRJNA774901 | 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

Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.

Project description:Estrogen and estrogen receptor alpha (ERα)-induced gene transcription is tightly associated with ERα-positive breast carcinogenesis. ERα-occupied enhancers, particularly super-enhancers, have been suggested to play a vital role in regulating such transcriptional events. However, the landscape of ERα-occupied super-enhancers (ERSEs) as well as key ERα-induced target genes associated with ERSEs remain to be fully characterized. Here, we defined the landscape of ERSEs in ERα-positive breast cancer cell lines, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSEs and cognate ERα target genes. RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key ERα target gene of BRD4-regulated ERSEs, which, in turn, is vital for ERα-induced gene transcriptional activation and malignant phenotypes through activating the RAS/RAF/MEK2/ERK/p90RSK/ERα phosphorylation cascade. Combination therapy with BRD4 and RET inhibitors exhibited additive effects on suppressing ERα-positive breast cancer both in vitro and in vivo, comparable with that of standard endocrine therapy tamoxifen. Furthermore, combination therapy re-sensitized a tamoxifen-resistant ERα-positive breast cancer cell line to tamoxifen treatment. Taken together, our data uncovered the critical role of a super-enhancer-associated positive feedback loop constituting BRD4/ERα-RET-ERα in ERα-positive breast cancer, and suggested that targeting components in this loop would provide a new therapeutic avenue for treating ERα-positive breast cancer in the clinic.

| S-EPMC9561272 | biostudies-literature

RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ERα

Project description:The molecular mechanisms of endocrine resistance in breast cancer remain poorly understood. Here we used PRO-seq to map the location of hundreds of genes and thousands of distal enhancers whose activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen identified a 16-fold transcriptional increase in glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which is both necessary and sufficient for resistance in MCF-7 cells. GDNF causes endocrine resistance by switching the active state of a bi-stable feedback loop from ERα signaling to GDNF-RET signaling. To catalyze this switch, we found that GDNF directly downregulates ERα transcription and activates the transcription factor EGR1, which, in turn, induces GDNF expression. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.

2018-02-22 | GSE93229 | GEO

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

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

2022-10-19 | GSE186646 | GEO

MOF forms a positive feedback regulation with ERα to suppress endometrial cancer progression

Project description:MOF is a histone acetyltransferase specific for H4K16 acetylation. It has been demonstrated that MOF is lower expressed in series of human cancers. However, the molecular mechanism underlying the detailed biological function of MOF in endometrial carcinomas (ECa) has not been fully defined. The estrogen receptor α (ERα) action plays a crucial role in endometrial cancer tumorigenesis and progression. Here, our data have demonstrated that estrogen/ERα induces MOF gene transcription, meanwhile MOF stabilizes ERα via acetylating ERα in ECa, indicating that MOF forms a positive feedback loop with ERα. In the whole genome-wide level, RNA microarray analyses have shown that MOF modulates a subset of endogenous ERα-regulated genes, such as apoptosis associated factor DRAM1 and oncogene FXYD3. Knockdown of MOF leads to a G2/M cell cycle arrest and promotes ECa cell growth and proliferation. MOF depletion promotes xenograft tumor growth in mice. In addition, our results have demonstrated that MOF expression is lower in ECa than that in benign endometrial tissues. Importantly, the expression of MOF is positively correlated with that of ERα in clinical samples. Cumulatively, our results suggest a positive feedback regulation involving MOF and ERα is essential for suppression of endometrial cancer.

2018-03-29 | GSE112419 | GEO

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