Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression
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ABSTRACT:
PROVIDER: PRJNA727316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14421865_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421865_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421866_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421866_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421867_1.fastq.gz | Fastqsanger.gz |
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Project description:Loss of REST function is seen in ~20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer. We then utilized gene knockdown in MCF-7 cells in the presence or absence of steroid hormones estrogen and/ progesterone followed by RNA sequencing in an attempt to understand the tumor suppressor role of REST in breast cancer. We show that REST directly regulates CEMIP (cell migration-inducing and hyaluronan-binding protein, KIAA1199) and MMP24 (matrix metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cells leads to significant upregulation of CEMIP and MMP24. In addition, we found REST binds to RE-1 sites (repressor element-1) within the genes and influences their transcription. Furthermore, we found that the estrogen receptor (ESR1) signaling pathway is activated in the absence of REST, regardless of hormone treatment. We demonstrate a critical role for the loss of REST in aggressive breast cancer pathogenesis and provide evidence for REST as an important diagnostic marker for personalized treatment plans.
2022-02-23 | GSE173857 | GEO
Project description:BackgroundBreast cancer is the most common malignancy in women, and is both pathologically and genetically heterogeneous, making early detection and treatment difficult. A subset of breast cancers express normal levels of REST (repressor element 1 silencing transcription factor) mRNA but lack functional REST protein. Loss of REST function is seen in ~ 20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer.MethodsTCGA data was analyzed for the expression of REST target genes in breast cancer patient samples. We then utilized gene knockdown in MCF-7 cells in the presence or absence of steroid hormones estrogen and/ progesterone followed by RNA sequencing, as well as chromatin immunoprecipitation and PCR in an attempt to understand the tumor suppressor role of REST in breast cancer.ResultsWe show that REST directly regulates CEMIP (cell migration-inducing and hyaluronan-binding protein, KIAA1199) and MMP24 (matrix metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cells leads to significant upregulation of CEMIP and MMP24. In addition, we found REST binds to RE-1 sites (repressor element-1) within the genes and influences their transcription. Furthermore, we found that the estrogen receptor (ESR1) signaling pathway is activated in the absence of REST, regardless of hormone treatment.ConclusionsWe demonstrate a critical role for the loss of REST in aggressive breast cancer pathogenesis and provide evidence for REST as an important diagnostic marker for personalized treatment plans.
| S-EPMC8851790 | biostudies-literature
Project description:Overexpression of REST has been implicated in brain tumors, ischemic insults, epilepsy, and movement disorders such as Huntington’s disease. However, owing to the lack of a conditional REST overexpression animal model, the mechanism of action of REST overexpression in these disorders has not been established in vivo. We created a REST overexpression mouse model using the human REST (hREST) gene. Our results using these mice confirm that hREST expression parallels endogenous REST expression in embryonic mouse brains. Further analyses indicate that REST represses the dopamine receptor 2 (Drd2) gene, which encodes a critical nigrostriatal receptor involved in regulating movement, in vivo. Overexpression of REST using Drd2-Cre in adult mice results in increased REST and decreased DRD2 expression in the striatum, a major site of DRD2 expression, and phenocopies the spontaneous locomotion deficits seen upon global DRD2 deletion or specific DRD2 deletion from indirect-pathway medium spiny neurons. Thus, our studies using this mouse model not only reveal a new function of REST in regulating spontaneous locomotion but also suggest that REST overexpression in DRD2-expressing cells results in spontaneous locomotion deficits.
2022-10-07 | GSE214743 | GEO
Project description:Uterine fibroids, benign tumors of the smooth muscle layer of the uterus, plague approximately 80% of the female population by age 50. While there have been efforts to understand the mechanism behind this pathophysiology, it largely remains unclear. Lack of preclinical animal models that recapitulate aberrant steroid hormone pathways in UL has significantly hampered the development of long-term hormonal therapies for uterine fibroids. In addition, cultured myometrial as well as leiomyoma smooth muscle cells rapidly silence both estrogen receptor alpha (ESR1) and progesterone receptor (PGR) expression through unknown mechanisms, further limiting in vitro mechanistic studies of UL. Previous work by our lab has determined the loss of REST, a master regulator of epigenetic gene silencing, in leiomyoma results in the upregulation of ESR1 targets and therefore estrogen signaling. Using ChIP-PCR, we find REST is directly associated with ESR1 genomic locus, playing a role in its epigenetic regulation. ChIP-seq analysis of Rest cKO mouse uterus samples reveal a global role for REST in the regulation of progesterone receptor target genes and highlights alterations in PGR binding within the Esr1 locus. Additionally, we find REST inhibition of ESR1 expression is regulated through upstream WNT planar cell polarity molecule, PRICKLE1. Based on REST’s role in silencing ESR1 expression in cultured myometrial cells, our results support the development of a potential cell culture method to maintain ESR1 expression through REST modulation. Finally, we establish a broad role for REST in epigenetic regulation relevant to leiomyoma pathophysiology.
2026-01-21 | GSE306878 | GEO
Project description:REST overexpression in mice causes deficits in spontaneous locomotion
| PRJNA886993 | ENA
Project description:Uterine Leiomyomas (UL) are benign tumors that arise in the myometrium of the uterus. The standard treatment option for UL is hysterectomy but hormonal treatment options are emerging in the field. However, since the pathogenesis of UL is poorly understood, hallmarks that predict long-term efficacy and safety of these treatment options remain largely undefined. We have reported previously that REST/NRSF target genes are aberrantly expressed due to the near ubiquitous loss of this epigenetic repressor in UL tumors. We show that ablation of Rest in the mouse uterus leads to UL phenotype and altered response to steroid hormones estrogen and progesterone. Additionally, we demonstrate that a large number of REST target genes dysregulated in UL as well as in Rest cKO mice, are also targets of progesterone receptor (PR). Importantly, we identify a direct interaction between REST and PR in the healthy myometrium. Rest cKO mouse model phenocopies human UL, including gene expression profiles of UL as well as tumor formation in the myometrium. Our findings emphasize the critical role loss of REST plays in disease pathogenesis and the altered response to steroid hormones seen in UL.
2022-10-12 | GSE178140 | GEO
Project description:Uterine Leiomyomas (UL) are benign tumors that arise in the myometrium of the uterus. The standard treatment option for UL is hysterectomy but hormonal treatment options are emerging in the field. However, since the pathogenesis of UL is poorly understood, hallmarks that predict long-term efficacy and safety of these treatment options remain largely undefined. We have reported previously that REST/NRSF target genes are aberrantly expressed due to the near ubiquitous loss of this epigenetic repressor in UL tumors. We show that ablation of Rest in the mouse uterus leads to UL phenotype and altered response to steroid hormones estrogen and progesterone. Additionally, we demonstrate that a large number of REST target genes dysregulated in UL as well as in Rest cKO mice, are also targets of progesterone receptor (PR). Importantly, we identify a direct interaction between REST and PR in the healthy myometrium. Rest cKO mouse model phenocopies human UL, including gene expression profiles of UL as well as tumor formation in the myometrium. Our findings emphasize the critical role loss of REST plays in disease pathogenesis and the altered response to steroid hormones seen in UL.
2022-10-12 | GSE178086 | GEO
Project description:ATM gene mutation carriers are predisposed to estrogen receptor (ER)-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis following ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. Following estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.
2023-06-01 | GSE218320 | GEO
Project description:Regulatory Role for Tumor Suppressor REST on Estrogen Receptor (ESR1) Expression and Leiomyoma Pathophysiology
| PRJNA1312842 | ENA
Project description:Neural differentiation of embryonic stem cells (ESCs) requires coordinated repression of the pluripotency regulatory programme and reciprocal activation of the neurogenic regulatory programme. Upon neural induction, ESCs rapidly repress expression of pluripotency genes followed by staged activation of neural progenitor and differentiated neuronal and glial genes. The transcriptional factors that underlie pluripotency are partially characterized, whereas those underlying neural induction are much less explored, and the factors that coordinate these two developmental programs are completely unknown. One transcription factor, REST (RE1 silencing transcription factor), has been linked with terminal differentiation of neural progenitors, and more recently and controversially, with control of pluripotency. Here, we show that in the absence of REST, coordination of pluripotency and neural induction is lost and there is a resultant delay in repression of pluripotency genes and a precocious activation of both neural progenitor and differentiated neuronal and glial genes. Further, we show that REST is not required for production of radial glia-like progenitors but is required for their subsequent maintenance and differentiation into neurons, oligodendrocytes and astrocytes. We propose that REST acts as a regulatory hub that coordinates timely repression of pluripotency with neural induction and neural differentiation. We have investigated the role of REST in the coupling of pluripotency and neural induction and neurogenesis using Rest-null mouse ESCs (mESCs) in conjunction with a novel mESC neural differentiation protocol. Differential expression between Rest-null ESCs and controls was tested using Illumina Mouse Ref-8 v2 BeadArray technology. Three replicates were used for Rest-null and three for control. Data analysis was performed using Bioconductor libraries beadarray and limma.
2011-12-08 | E-GEOD-34244 | biostudies-arrayexpress