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The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple-negative breast cancer

ABSTRACT: Development of targeted therapies will be a critical step towards reducing the mortality associated with triple-negative breast cancer (TNBC). To achieve this, we searched for targets that met three criteria: (1) pharmacologically targetable, (2) expressed in TNBC, and (3) expression is prognostic in TNBC patients. Since nuclear receptors have a well-defined ligand-binding domain and are thus highly amenable to small-molecule intervention, we focused on this class of protein. Our analysis identified TLX (NR2E1) as a candidate. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in the pro-proliferative KRAS signaling pathway as well as epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell proliferation, migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. Taken together, our work indicates that TLX retards the progression of TNBC. Several ligands have been shown to regulate the transcriptional activity of TLX, providing a framework for the future development of this receptor for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196105 | GEO | 2022/07/11

REPOSITORIES: GEO

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Tlx (nr2e1)-dependent gene expression in adult neural stem cells

Project description:Tlx (nr2e1) is an orphan nuclear receptor that is highly expressed in proliferating neural stem cells (NSCs) in the adult mouse forebrain. The goal was to identify Tlx-regulated genes in this specific cell population. Two populations of Tlx-positive neural stem cells were isolated from 2-month-old male mice based on a LacZ marker that was knocked into the Tlx locus. The first population, Tlx(f/Z;CreER), contains a floxed allele of Tlx (f), the LacZ marker (Z), and a CreER fusion transgene. Addition of tamoxifen (4OH-tamoxifen) into this NSC population leads to Cre-mediated deletion of the floxed allele of Tlx. The second NSC population, Tlx(f/Z), does not contain a CreER transgene; thus it does not respond to tamoxifen treatment and was used as a control. Keywords: Nuclear receptor-dependent gene expression

2008-12-01 | GSE9981 | GEO

Transcription profiling of mouse Tlx-positive neural stem cells isolated from 2-month-old male to investigate Tlx (nr2e1)-dependent gene expression in adult neural stem cells

Project description:Tlx (nr2e1) is an orphan nuclear receptor that is highly expressed in proliferating neural stem cells (NSCs) in the adult mouse forebrain. The goal was to identify Tlx-regulated genes in this specific cell population. Two populations of Tlx-positive neural stem cells were isolated from 2-month-old male mice based on a LacZ marker that was knocked into the Tlx locus. The first population, Tlx(f/Z;CreER), contains a floxed allele of Tlx (f), the LacZ marker (Z), and a CreER fusion transgene. Addition of tamoxifen (4OH-tamoxifen) into this NSC population leads to Cre-mediated deletion of the floxed allele of Tlx. The second NSC population, Tlx(f/Z), does not contain a CreER transgene; thus it does not respond to tamoxifen treatment and was used as a control. Experiment Overall Design: Total RNA samples from two biological replicates were collected at 36 hr or at 60 hr after tamoxifen or vehicle treatment. Total of 16 samples were used to analyze the global gene expression changes using Affymetrix chips.

2009-01-13 | E-GEOD-9981 | biostudies-arrayexpress

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Project description:We previously showed that the orphan nuclear hormone receptor, TLX (also known as NR2E1), selectively modifies the output of IFN-gamma-driven, STAT1-dependent gene expression. Since IFN-gamma and STAT1 are also known to regulate myeloid cell development and function, we tested whether ectopic expression of TLX or COUPTF2 (a closely related orphan nuclear receptor) might influence hematopoietic differentiation. Indeed, TLX promotes lineage commitment toward myeloid development and suppresses erythropoiesis, phenocopying IFN-gamma treatment. Moreover, TLX expression in our assay is sufficient to activate a proinflammatory transcriptional program with two hallmarks: differential regulation of STAT1-dependent genes, and suppression of an anti-inflammatory program in favor of a fatty acid signature – a process known to be essential for cellular remodeling during macrophage maturation and phagocytosis. These results demonstrate an important role for a new nuclear hormone receptor in STAT1 signaling, and link TLX to myeloid lineage commitment and function.

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The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple-negative breast cancer

Project description:The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple-negative breast cancer

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Expression data from glioblastoma stem cells

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Genome-wide analysis of the function of Tlx in regulating mouse brain glioma gene expression

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Genome-wide analysis of the function of Tlx in regulating mouse brain glioma gene expression

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Nuclear orphan receptor TLX affects gene expression in pancreatic beta cells

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Nuclear orphan receptor TLX affects gene expression in pancreatic beta cells

Project description:Using Illumina’s digital gene expression (DGE) system, we investigated the transcriptional response to TLX overexpression in beta cells. Finally, an average of 13,791,918 and 12,476,623 reads of high quality clean tags were obtained from control and TLX-overexpressing beta cells, respectively. Results reveals that overexpression of TLX resulted in suppression of 176 genes by ?50%, and also results in ?2-fold upregulation of 49 genes. Expression profiling of stable TLX overexpressing MIN6 cells and control cells by high throughput sequencing

2015-03-06 | E-GEOD-66551 | biostudies-arrayexpress

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