MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE202316 | GEO | 2022/05/06
REPOSITORIES: GEO
Similar Datasets
Project description:Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3, BIRC5, BRCA2 and RAD51. The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC.
| S-EPMC9102308 | biostudies-literature
Project description:MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation
| PRJNA835447 | ENA
Project description:In this study, we comparatively analyzed the members of the miR-449 family (miR-449a, miR-449b, and miR-449c) with regards to their target genes and functional effects in hepatocellular carcinoma (HCC). Microarray analysis after transient transfection of miR-449a, miR-449b, and/or miR-449c in the HCC cell line HLE identified putative target genes of miR-449a, miR-449b, and miR-449c. For transient overexpression of miRNAs, the HCC cell line HLE was transfected with 50 nM Allstars Negative Control or miScript miRNA mimics. MiRNA mimics for miR-449a, miR-449b, and miR-449c were either single transfected or cotransfected in equimolar amounts (16.7 nM each). Global mRNA expression profiling was performed utilizing pooled RNA of three biological replicates per microarray and two microarrays per condition.
2015-11-06 | E-GEOD-74710 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous disease representing the most aggressive breast cancer (BC) subtype. Lack of Estrogen Receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu) expression makes TNBC immune to common therapies, significantly limiting the treatment options and suggesting the need to identify novel therapeutic targets. It was previously reported that Estrogen Receptor beta (ERβ) is expressed in a fraction of TNBC patients, where its presence correlates with improved patient outcome. Recently, we demonstrated an oncosuppressive ERβ effect in TNBC cell models expressing exogenous ERβ. On the other hand, it was shown that ERβ is involved in miRNA-mediated gene regulation in hormone-responsive BC cells, suggesting similar effect also in TNBC. To verify this hypothesis, we performed small non-coding RNA (sncRNA) sequencing on three engineered cell lines belonging to different TNBC molecular subtypes. ERβ-specific changes of sncRNA profile revealed that the major part of deregulated molecules are subtype specific, with only few commonly regulated ones. In order to validate the obtained results, we performed sncRNA profiling of 12 ERβ positive and 32 ERβ negative TNBC tissues, whose receptor status was assessed by immunohistochemistry in our previous research. Also here, ERβ-specific group of deregulated sncRNAs was identified. Interestingly, comparison of obtained in vitro and in vivo results revealed 2 differentially expressed miRNAs, displaying the same behavior in all three analyzed cell lines and tissues. In concordance with our previous results, IPA signaling pathway analysis performed on genes targeted by deregulated miRNAs highlighted downregulation of cholesterol biosynthesis pathway and upregulation of several signaling processes. Taken together, these findings suggest that ERβ is able to exert its oncosuppressive role in TNBC through miRNA-mediated regulation of gene expression.
2020-04-04 | E-MTAB-8807 | biostudies-arrayexpress
Project description:To investigate the Nexturastat A effects on chromatin structure which disrupt phospho-HDAC6 LLPS in triple-negative breast cancer (TNBC), we conducted the analysis of Hi-C in TNBC cells treated with or without Nexturastat A.
2024-05-09 | GSE254213 | GEO
Project description: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.
2022-07-11 | GSE196105 | GEO
Project description:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial to mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting. Sub-confluent cultures of MDA-MB-231 cells were treated with 1µM Tat-SID peptide or 1µM Tat-Scr scrambled control peptide for 24hr.
2015-11-02 | E-GEOD-73278 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial to mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting. Mononucleosomes from MDA-MB-231 cells were isolated and ChIP with H3K4me3 antibody. DNA from Input and ChIP samples was purified and sequenced on Illumina Hiseq.
2015-11-02 | E-GEOD-73869 | biostudies-arrayexpress
Project description:To further elucidate the role of phospho-HDAC6 LLPS in transcriptional regulation, we performed RNA-seq experiments in TNBC cells treated with Nexturastat A or HDAC6 knockdown
2024-05-09 | GSE253744 | GEO
Project description:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options and a poor prognosis. TNBC exists widely reprogrammed lipid metabolism, and its metabolic-associated proteins and oncometabolites are promising as potential therapeutic targets. Dandelion (Taraxacum mongolicum) is a classical herbal medicine used to treat breast diseases based on traditional Chinese medicine theory and was reported to have antitumor effects and lipid regulatory capacities. Our previous study showed that dandelion extract was effective against TNBC. However, whether dandelion extract could regulate the lipid metabolisms of TNBC and exert its antitumor effects via interfering with lipids metabolism remained unclear. In this study, an integrated approach combined with network pharmacology and multi-omics techniques (including proteomics, metabolomics, and lipidomics) was performed to investigate the potential regulatory mechanisms of dandelion extract against TNBC. We first determined the antitumor effects of dandelion extract in vitro and in vivo. Then, network pharmacology analysis speculated the antitumor effects involving various metabolic processes, and the multi-omics results of the cells, tumor tissues, and plasma revealed the changes in the metabolites and metabolic-associated proteins after dandelion extract treatment. The alteration of glycerophospholipids and unsaturated fatty acids were the most remarkable types of metabolites. Therefore, the metabolism of glycerophospholipids and unsaturated fatty acids, and their corresponding proteins CHKA and FADS2, were considered the primary regulatory pathways and biomarkers of dandelion extract against TNBC. Subsequently, experimental validation showed that dandelion extract decreased CHKA expression, leading to the inhibition of the PI3K/AKT pathway and its downstream targets, SREBP and FADS2. Finally, the molecular docking simulation suggested that picrasinoside F and luteolin in dandelion extract had the most highly binding scores with CHKA, indicating they may be the potential CHKA inhibitors to regulate glycerophospholipids metabolisms of TNBC. In conclusion, we confirmed the antitumor effects of dandelion extract against TNBC cells in vitro and demonstrated that dandelion extract could interfere with glycerophospholipids and unsaturated fatty acids metabolism via downregulating the CHKA expression and thus inhibiting PI3K/AKT/SREBP/FADS2 axis.
2022-10-14 | PXD035797 | Pride