Inhibition of TNBC metastasis by Gpx1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8586200_1.fastq.gz | Fastqsanger.gz | |||
| SRR8586200_2.fastq.gz | Fastqsanger.gz | |||
| SRR8586201_1.fastq.gz | Fastqsanger.gz | |||
| SRR8586201_2.fastq.gz | Fastqsanger.gz | |||
| SRR8586202_1.fastq.gz | Fastqsanger.gz |
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Project description:Gpx1 plays a vital role in the metastasis of TNBC cells by regulating cell adhesion. Depletion of Gpx1 reduces the survival, migration, and invasion of TNBC cells in vitro. Transcriptomic and signaling pathway analyses demonstrate that depletion of Gpx1 essentially impairs cell adhesion/spreading by down-regulating FAK/c-Src activation.
2019-11-30 | GSE126675 | GEO
Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor Sp1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.
2022-11-10 | GSE217474 | GEO
Project description:Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed by the absence of progesterone receptor (PR). Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyper-acetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.
2024-12-20 | GSE283282 | GEO
Project description:CCL5/CCR5 axis is an immunotherapeutic target for triple-negative breast cancer (TNBC). However, the signaling mechanism is poorly understood and its antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a specific and more potent inhibitor than maraviroc. It significantly reduced TNBC tumor growth in an immunologically dependent manner, and lung metastasis in a cell-intrinsic way. Mechanistically, CCR5 was co-expressed with Yes-associated protein 1 (YAP1) in TNBC patients. RNA-sequencing and expression silencing further revealed that CCR5 promoted the expression of YAP1 through HIF-1α in TNBC cells, and through YAP1 to regulate β-catenin, ZEB1/ZEB2 for metastasis, as well as CXCL16 and CXCL8 for immune cell migration and tumor growth. In essence, verteporfin may have potential immunotherapeutic applications for diseases co-expressing CCR5 and YAP1 such as TNBC. The HTS assay can be adapted for unveiling antagonists of broader signaling pathways.
2024-01-25 | GSE222052 | GEO
Project description:POGZ loss increases TGFβ signaling and potentiates TNBC metastasis
| PRJNA1039840 | ENA
Project description:EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis
| PRJNA899075 | ENA
Project description:Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, characterized by a lack of therapeutic options. Dysregulation of alternative splicing plays a pivotal role in tumorigenesis and metastasis. Serine/arginine-rich (SR) proteins, essential components of the spliceosome, undergo phosphorylation by Cdc2-like kinases (CLKs). Here we explored the impact of pharmacological inhibition of CLKs using a novel inhibitor, T-025, on TNBC cell proliferation and migration. Methods In this study, we evaluated the anti-proliferative and anti-migratory efficacy of T-025 in a spectrum of TNBC cell lines. Fluorescent reporter cell lines and flowcytometry were used to determine the effect of T-025 on cell cycle. Live-cell imaging and photobleaching experiments were conducted to determine the subnuclear localization of SRSF7-GFP and its dynamic mobility. Pulldown/MS was used to uncover the impact of T-025 on SRSF7 interactome. Deep RNA sequencing was performed to unravel the differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) upon T-025 treatment. Results T-025 exhibited a potent anti-proliferative effect, particularly in highly proliferative TNBC cell lines. Treatment with T-025 induced cell cycle arrest in the G1-S phase, resulting in an increased proportion of aneuploidy cells and cells with 4N DNA. T-025 significantly inhibited cell migration in highly migratory TNBC cell lines. T-025 led to the accumulation of SRSF7-GFP at nuclear speckles, restricting its mobility. SRSF7 interacted more with nuclear-speckle-residing proteins, while less with RNA helicases and polymerases upon T-025 treatment. Enhanced interactions between SRSF7 and other phosphorylated SR proteins localized at nuclear speckles were observed. RNA sequencing uncovered multiple DEGs and ASGs upon T-025 treatment, which were significantly enriched in pathways related to cell division, RNA splicing and cell migration. Conclusions We demonstrated the pivotal role of CLKs inhibition in the proper function of SR proteins and RNA splicing in TNBC cell lines. CLKs inhibition leads to the accumulation of splicing factors at nuclear speckles and stalls their release to splicing sites, resulting in the RNA splicing reprogramming of a large number of genes involved in cell division and migration. Our findings provide evidence that CLKs inhibition could be a promising therapeutic approach for TNBC patients.
2025-08-04 | PXD058273 | Pride
Project description:The pogo transposable element derived zinc finger protein, POGZ, is notably associated with autism-like or intellectual disabilities through its role in gene transcription. Indeed, many proteins involved in neurological development are often dysregulated in cancer. We provide the first experimental evidence that POGZ influences the growth and metastatic spread of triple negative breast cancers (TNBC). Utilizing a well-characterized immunocompetent model of TNBC, we show that POGZ exerts a dual role, both as a tumor promoter and metastasis suppressor. Mechanistically, we show that POGZ loss potentiates TGFβ pathway activation in TNBC, to exert cytostatic effects while simultaneously increasing the mesenchymal and migratory properties of breast tumors. Finally, we demonstrate that whereas POGZ levels are elevated in human breast cancers, the most aggressive TNBC tumors, including those with increased mesenchymal and metastatic properties, dampen POGZ levels, associated with inferior clinical outcomes. Combined these data suggest that POGZ is a critical regulator of the early stages of metastatic cascade
2024-07-31 | GSE247628 | GEO
Project description:N-acylsphingosine amidohydrolase (ASAH1) expression is elevated in many cancer types including breast cancer. Therefore, we analyzed the role of ASAH1 in TNBC. Inhibition of ASAH1 expression in TNBC cell lines resulted in decreased tumor growth and metastasis
2024-07-31 | GSE247750 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, associated with poor response to therapies and high mortality. We identify that phosphodiesterase 7A (PDE7A) is overexpressed in the majority of TNBC, and a higher level of PDE7A associates with poor prognosis. The PI3K/AKT pathway, via the transcription factor IRF1, stimulates the expression of PDE7A in TNBC cells. PDE7A inhibition attenuates TNBC growth in both cell culture and mouse models of TNBC. Inhibition of PDE7A suppresses de novo pyrimidine biosynthesis, in part through the downregulation of the enzyme dihydroorotate dehydrogenase (DHODH). DHODH suppression attenuates TNBC tumor growth, mirroring the effects of PDE7A inhibition, and ectopic DHODH expression rescues PDE7A-inhibition-induced tumor suppression. Pharmacological co-targeting of PDE7A and DHODH potently inhibits TNBC tumor growth and metastasis. These findings identify the PDE7A→ DHODH→ de novo pyrimidine biosynthesis pathway as a key driver of TNBC, offering additional therapeutic opportunities for TNBC patients.
2025-09-15 | GSE192830 | GEO