Ontology highlight
ABSTRACT:
PROVIDER: PRJNA742841 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15011446_1.fastq.gz | Fastqsanger.gz | |||
| SRR15011446_2.fastq.gz | Fastqsanger.gz | |||
| SRR15011447_1.fastq.gz | Fastqsanger.gz | |||
| SRR15011447_2.fastq.gz | Fastqsanger.gz | |||
| SRR15011448_1.fastq.gz | Fastqsanger.gz |
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Project description:Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive, metastatic, and clinically challenging breast cancer subtype with worst prognosis. Despite survival dependency on the proteasome pathway genes, the FDA-approved proteasome inhibitors induced minimal clinical response in TNBC patients due to weaker proteasome inhibition. Here, we show that a novel proteasome inhibitor Marizomib (Mzb), inhibited multiple proteasome catalytic activities and induced better anti-tumor response in TNBC cell line and patient-derived xenografts alone and in combination with a standard-of-care chemotherapy, doxorubicin. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Development of metastatic disease, especially brain metastasis, remains a reason for a greater mortality rate amongst TNBC patients. Mzb reduces lung and brain metastasis in vivo by reducing circulating tumor cells and the expression of multiple epithelial-to-mesenchymal genes. We also demonstrate that Mzb-induced OXPHOS inhibition upregulates glycolysis to fulfill the metabolic demand of TNBC cells and hence, combined inhibition of glycolysis with Mzb leads to a synergistic anti-cancer activity in vivo. Collectively, our data provide a strong rationale for the clinical evaluation of Mzb in primary and metastatic TNBC patients.
2020-05-27 | PXD015141 | Pride
Project description:<p>Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.</p>
2022-05-31 | MTBLS4709 | MetaboLights
Project description:Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and high propensity for brain metastasis, often exhibiting resistance to standard treatments. In this study, we conducted a preliminary screening of potential therapeutic agents and identified chlorpromazine (CPZ) as a promising candidate for treating TNBC and its brain metastases. In vivo experiments demonstrated that CPZ robustly suppressed tumor growth and metastasis, particularly in lung and brain models, without affecting mouse body weight, indicating a favorable safety profile. Importantly, CPZ enhanced the efficacy of standard therapeutic agents such as vinorelbine and anti-PD-1 antibody. Mechanistically, CPZ induced G2/M phase arrest and triggered mitochondria-mediated intrinsic apoptosis in TNBC cells, characterized by increased ROS levels, decreased mitochondrial membrane potential, and alterations in related proteins. Furthermore, TMT-labeled quantitative proteomics analysis revealed that CPZ triggered incomplete autophagy and activated PINK1-Parkin-mediated mitophagy, marked by mitochondrial dysfunction in structure and physiological function. Inhibiting autophagy/mitophagy augmented CPZ's anticancer effects, indicating these processes may have protective roles. Overall, our study highlights the dual function of CPZ in suppressing TNBC growth and metastasis, positioning it as a promising candidate for treating this aggressive cancer. Additionally, targeting autophagy/mitophagy may serve as an effective strategy to enhance anticancer therapies against TNBC.
2025-02-04 | PXD060502 |
Project description:Many oncogenic transcription factors (TFs) are considered to be undruggable due to their reliance on large protein-protein and protein-DNA interfaces. TFs like hypoxia-inducible factors (HIFs) and X-box binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to UPRE/HRE motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the bZIP domain of XBP1 and recognize the UPRE/HRE motif. A lead molecule, STR22, binds UPRE/HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1a binding to HRE-containing promoters/enhancers, inhibits hypoxia-induced gene expression and blocks pro-tumorigenic phenotypes in TNBC cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.
2024-06-22 | GSE198157 | GEO
Project description:Hypoxia-induced ncRNA transcriptome in TNBC cells
| PRJNA604033 | ENA
Project description:Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors, is often related to increased extracellular vesicle (EV) secretion and favors cell invasion, which is a crucial step for metastasis. Cell invasion is a complex process in which cell morphology is altered due to F-actin cytoskeleton polarization and the establishment of dynamic focal adhesion spots, which coupled with ECM remodeling enables cells to migrate through tissues seeking a new developmental niche. In our in-depth investigation over the invasive properties triggered by TNBC-derived hypoxic small EVs (SEVh) in vitro, we analyzed the morphological, phenotypical and proteomic distinctions promoted by hypoxia and/or SEVh signaling in TNBC cells. SEVh was fully characterized and showed a distinct proteome and abundance profile from its normoxic counterparts. SEVh promotes invasive behaviors exclusively in normoxia, including pro-migratory morphology, invadopodia development, ECM degradation and gelatinase secretion, which indicates the importance of SEVh response on hypoxic settings in tumor progression. In hypoxia, SEVh was responsible for proteolytic and catabolic pathway inducement, interfering with integrin availability and gelatinase expression. Protein profiling of SEVh-treated, normoxic cells indicate a baseline favoring of metabolic processes and cell cycle, modulating cell health away from apoptotic pathways that are enriched in hypoxia. Overall, our results demonstrate the importance of hypoxic signaling via SEV in a tumoral setting for the early establishment of metastasis.
2022-11-01 | PXD035244 | Pride
Project description:Triple-negative breast cancer (TNBC) is a malignant type of breast cancer. Owing to the lack of expression of receptors that serve as molecular targets for standard therapy for breast cancer, conventional cytotoxic chemotherapy is the primary treatment option for TNBC. However, TNBC exhibits a high degree of genomic heterogeneity, rendering it resistant to chemotherapy. Therefore, there is an urgent need to identify novel therapeutic targets for the treatment of TNBC. Advances in massively parallel sequencing technology have enabled the identification of cancer cell-specific gene expression patterns and epigenetic alterations that regulate their expression. Cancer cell-specific super-enhancers (SEs) have been identified as effective therapeutic targets for cancer. In this study, we identified the functional roles of epigenetic changes and their regulatory mechanisms in TNBC cells. TNBC cell-specific SEs were formed near several genes that contribute to malignant cancer cell acquisition. We found that the transcription factor OCT-2 (encoded by POU2F2) was responsible for the formation of SEs and the expression of genes encoded in the vicinity of the SE regions. Overexpression of POU2F2 enhances the metastasis of TNBC cells in mice and their expression is highly correlated to poor prognosis of TNBC patients. Our findings provide a new insight into cancer cell-specific epigenetic changes induced by OCT-2, which trigger the progression of TNBC, and suggest possible candidates that could be targeted for the treatment of TNBC.
2025-05-14 | GSE291650 | GEO
Project description:We identified sphingosine kinase 1 (SPHK1) as a top candidate. SPHK1-overexpression in human TNBC cell-line promotes spontaneous metastasis to lungs in nude mice. Moreover, genetic knockdown of SPHK1 in TNBC patient-derived xenograft (PDX) cells and TNBC cell-line decreases spontaneous metastasis to lungs in nude mice. SPHK1 regulates the FSCN1 gene expression in order to drive metastasis. Mechanistically, SPHK1 transcriptionally upregulates metastasis-promoting FSCN1 gene expression via NFκB activation to promote metastasis. SPHK1/NFκB/FSCN1 signaling pathway activation is associated with distance metastasis and poor clinical outcome in TNBC patients.
2019-03-21 | GSE128624 | GEO
Project description:Coactivator associated arginine methyltransferase 1 has been reported to play paramount roles in estrogen receptor alpha (ERα)-positive breast cancer. It promotes breast cancer development and metastasis. However, little research about CARM1 has been focused on triple-negative breast cancer (TNBC). Here, we report that CARM1 promotes proliferation, epithelial-mesenchymal transition (EMT) and stemness in TNBC. CARM1 transactivates Hypoxia-inducible factor 1 subunit alpha (HIF1A) and is physically associated with it. They function together in a concerted complex to regulate downstream targets and promote the carcinogenesis and metastasis of TNBC.
2024-02-24 | GSE167394 | GEO
Project description:Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of chemoresistant TNBC patients with different prognosis. In this study, 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital) are chosen for study We used gene expression data of TNBC patients with residual disease and different prognosis to molecularly define the clinically relevant subgroups, and developed a 7-gene prognostic signature for chemoresistant TNBCs
2013-01-15 | E-GEOD-43502 | biostudies-arrayexpress