The EN1 transcription factor drives neural features and brain metastases in triple negative breats cancer (TNBC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120957 | GEO | 2019/08/22
REPOSITORIES: GEO
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Project description:Breast cancers lacking receptors for estrogen, progesterone or HER2 on their cell surface are called triple-negative breast cancers (TNBCs). TNBCs account for ~15-20% of all invasive breast cancers and do not benefit from anti-hormonal or anti-HER2 treatments. Although patients with TNBC can initially respond to chemotherapy, they do have worse overall prognosis compared to other breast cancer subtypes. Unfortunately, TNBCs lack clear targetable ‘driver’ oncogenes. Thus, there is an unmet need for strategies to improve the therapeutic options for these patients. We used microarrays to assess differences in gene expression in triple-negative breast cancer cells in response to the platinum-based chemotherapeutic agent cisplatin. The purpose was to find drug induced changes in gene expression level that could differentiate cisplatin sensitive from cisplatin resistant TNBC cell lines.
2017-08-26 | GSE103115 | GEO
Project description:Development of targeted therapies for triple-negative breast cancer (TNBC) has failed at least in part because of the heterogeneity of these poor prognosis cancers. To identify common dependencies of basal-like TNBCs, we performed a targeted siRNA lethality screen in 7 human breast cancer cell lines focusing on 154 previously identified dependency genes of one basal-A TNBC line. Thirty genes were shared basal-A TNBC dependencies. Genes for proteins involved in RNA splicing, in particular those associated with the U4/U6.U5 tri-snRNP complex (e.g. PRPF8, PRPF38A), were prominent shared dependencies. Spliceosome genes were commonly up-regulated in primary basal-like TNBCs. Knockdown of PRPF8 or PRPF38A led to widespread intronic retention, expression of immune system genes and aberrant splicing of transcripts involved in protein translation, proteasome function, mitosis and apoptosis, including the TNBC dependency gene MCL1. These transcripts were susceptible to inhibition of RNA splicing more generally, since they were similarly affected by the RNA splicing inhibitor drug E7107. In particular, E7107 caused splicing of MCL1 to its pro-apoptotic splicing variant in multiple cell lines, killed MCL1-dependent basal-A cells in vitro, and suppressed the growth of 2 basal-A cell-lines and 1 of 2 patient-derived basal-like TNBC xenografts in vivo. Thus, TNBCs critically rely on RNA splicing and could be susceptible to RNA splicing inhibitors.
2018-01-01 | GSE90519 | GEO
Project description:Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers (TNBC) represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of TNBC remains largely unexplored. This study has investigated miRNA expression profiles in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. 71 miRNAs were differentially expressed in TNBC, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that miRNAs involved in the initiation of TNBC are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive TNBCs were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases. miRNA expression profiles were examined in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues
2014-11-24 | E-GEOD-38167 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
2021-07-07 | PXD021726 | Pride
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with low 5-year survival rates, high 3-year recurrence rates, and no known therapeutic targets. Recent studies have indicated TNBCs possess an altered metabolic state with higher rates of glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and increased generation and utilization of TCA cycle intermediates. Here we utilized a label-free quantitative proteomics approach to investigate the effects of a methanolic extract from the plant Lippia origanoides (L42) on MDA-MB-231 TNBC cells. L42 dysregulated mitochondrial OXPHOS by targeting Complex I of the electron transport chain and suppressed cellular metabolism by targeting key TCA cycle enzymes and mitochondrial lipid and amino acid metabolic pathways. Our study also revealed that treatment with L42 was seen to activate the stress response, and pathways related to cell cycle progression and DNA repair. Overall, our results reveal new compelling evidence that L42 triggers rapid, irreversible apoptosis in MDA-MB-231 cells by effectively 'starving' the cells of metabolites and ATP. We continue to study the specific bioactive components of L42 in the search for novel, highly effective mitochondrial inhibitors to selectively target TNBC.
2018-03-13 | MSV000082159 | MassIVE
Project description:To identify Differentially methylated regions (DMRs) in TNBCs, we performed methyl binding domain protein 2 enrichment of DNA followed by massively parallel sequencing (MBD-seq) using 10 breast tumors and 10 matched normal samples for each of the four subtypes (LumA, LumB, HER2, and TNBC), classified according to ER, PR, and HER2 expression. ~~. 468 genes were significantly hypomethylated and 353 genes were significantly hypermethylated in promoter and CDS regions in only TNBC.
2023-06-30 | GSE116877 | GEO
Project description:Mixed Lineage Kinase 3 (MLK3) is a viable emerging target for neoplastic diseases; however, it is uncertain whether its activators or inhibitors can act as anti-neoplastic agents. Previously, we reported that the kinase activity of MLK3 was significantly higher in triple-negative breast cancer (TNBC) than hormone receptor-positive human breast tumors where estrogen inhibits MLK3 kinase activity and provides a survival advantage to ER+ breast cancer cells. Here, we identified that in TNBC, the higher MLK3 kinase activity paradoxically promotes cell survival via activating the downstream PAK1-NF-kB axis. The MLKs/MLK3 inhibitors, CEP-1347, and URMC-099 induced cell death in TNBC but not in hormone receptor-positive breast cancer cells. The MLKs/MLK3 inhibitors reduced TNBC cell line and patient-derived xenografts’ tumor burden. The MLKs/MLK3 inhibitors also decreased MLK3, PAK1, and NF-kB protein expression and activation, prompting cell death in breast PDXs. The RNA-seq analyses indicated several genes downregulated upon MLKs/MLK3 inhibition in tumors. Significantly NGF/TrkA MAPK pathway was enriched in tumors undergoing tumor reduction by CEP-1347 and URMC-099. The tumors or cell lines that did respond to MLKs/MLK3 inhibitors had higher TrkA expression, and TrkA overexpression in the presence of MLK3 sensitized the TNBC cell line that initially did not respond to MLKs/MLK3 inhibitors. These results suggest that the functions of MLK3 in cancer cells are dependent on downstream targets/signaling, and rationalized decision needs to be made before using its inhibitor in different breast cancer subtypes. Our data also highlight that MLK3 inhibitor warrants further investigation for treating TNBC.
2023-03-01 | GSE188947 | GEO
Project description:Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers (TNBC) represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of TNBC remains largely unexplored. This study has investigated miRNA expression profiles in 31 primary TNBC cases and in 13 lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. 71 miRNAs were differentially expressed in TNBC, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that miRNAs involved in the initiation of TNBC are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive TNBCs were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases.
2014-11-24 | GSE38167 | GEO
Project description:The aggressive triple negative breast cancers (TNBCs), which lack estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), comprise a high-risk subset of human breast cancers which remain poorly characterized and lack effective treatments. While meta-analyses have recently suggested the complexity of these tumors, no robust phenotypes have been defined. We identified four distinct subtypes through gene expression analyses of 198 TNBCs (84 Discovery, 114 Validation). We then classified 221 publically available TNBCs profiled on the same mRNA expression array. All three sets supported stratification of tumors by cell cycle (Subtype 1 Luminal – FOXA1, LUM), DNA repair (Subtype 2, Mesenchymal – ADIPOQ, MES), downregulated immunological (Subtype 3, Basal-Like – SOX10/8, BL), and upregulated immunological (Subtype 4, Basal Immune – STAT1, BI) signaling pathways. Additional classified data sets demonstrate significantly lower risk of relapse and death with BI tumors, and highest risk with BL tumors, even after correction with known risk factors. DNA copy number profiling of our primary study set produced optimal differentiation of the LUM subtype from the remaining tumors, and drove expression of FGFR2 and CDK1 in BL and BI subtypes. Subtype-specific targets include MUC1 in LUM tumors, CTLA4 in BI tumors, and a potential dependence of MES tumors on NTRK2, DDR2, PDGFRA, TEK, and ADRB2, which, upon validation, could enable targeted treatment with tyrosine-kinase inhibitors and beta-blockers. These findings further define TNBCs and provide the rationale for studies targeting agents against these tumor subtypes, thereby enabling a higher potential for preventive efficacy in patients with TNBC.
2015-12-25 | GSE76339 | GEO
Project description:The expression levels of JMJD6 and its correlation with H2A.XY39ph differed in TNBC and non-TNBC cells. In addition, we have previously shown that H2A.XY39ph levels are positively correlated with tumor size, histological grade and advanced TNM stage in breast cancer. To analyze the role of JMJD6 in regulating the characteristics of different subtypes of breast cancer, the transcriptomes of TNBC cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared. We speculate that JMJD6 overexpression cause autophagy pathway activation in TNBC via enhancing ATG genes expression.
2023-10-01 | E-MTAB-6517 | biostudies-arrayexpress