DNA methylation analysis of breast cancer Hs578T cells with TET1 knockout
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE115685 | GEO | 2018/06/28
REPOSITORIES: GEO
Similar Datasets
Project description:Both gains and losses of DNA methylation are common in cancer but the factors controlling this methylation balance remain unclear. Triple negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU is one of the most hypomethylated cancers observed. In search for an explanation for this, we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer specific oncogenic pathways including PI3K, EGFR and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K-mTOR pathway. CRISPR mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a novel druggable target for therapeutic intervention.
2018-06-26 | GSE115578 | GEO
Project description:DNA hypermethylation is known to contribute to the formation of cancer. However, DNA hypomethylation has received far less attention and the factors controlling the balance between hypo and hypermethylation and its impact on tumorigenesis remains unclear. Triple negative breast cancer (TNBC), a subtype of breast cancer that does not overexpress the hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Importantly, TNBCs are often a therapeutic challenge because of advanced presentation and lack of targeted therapies. TET1 is a DNA demethylase that regulates DNA methylation, hydroxymethylation and gene expression. We found that TET1 is specifically overexpressed in TNBC, where it is associated with hypomethylation and a worse overall survival. Further, we uncover an intricate network connecting TET1 expression to maintaining activation of cancer specific pathways, including PI3K, EGFR and PDGF. In TET1 KO cells, we observed reduced phospho-4EBP1 and decreased expression of genes in the PI3K pathway, suggesting loss of PI3K-mTOR activity is concomitant with loss of TET1. Additionally, TET1 KO cells have reduced cellular proliferation and migration. Our work establishes TET1 as an oncogene that contributes to the aberrant hypomethylation observed in cancer and suggests TET1 could serve as a novel druggable target for therapeutic intervention.
2018-06-28 | GSE100640 | GEO
Project description:DNA hypermethylation is known to contribute to the formation of cancer. However, DNA hypomethylation has received far less attention and the factors controlling the balance between hypo and hypermethylation and its impact on tumorigenesis remains unclear. Triple negative breast cancer (TNBC), a subtype of breast cancer that does not overexpress the hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Importantly, TNBCs are often a therapeutic challenge because of advanced presentation and lack of targeted therapies. TET1 is a DNA demethylase that regulates DNA methylation, hydroxymethylation and gene expression. We found that TET1 is specifically overexpressed in TNBC, where it is associated with hypomethylation and a worse overall survival. Further, we uncover an intricate network connecting TET1 expression to maintaining activation of cancer specific pathways, including PI3K, EGFR and PDGF. In TET1 KO cells, we observed reduced phospho-4EBP1 and decreased expression of genes in the PI3K pathway, suggesting loss of PI3K-mTOR activity is concomitant with loss of TET1. Additionally, TET1 KO cells have reduced cellular proliferation and migration. Our work establishes TET1 as an oncogene that contributes to the aberrant hypomethylation observed in cancer and suggests TET1 could serve as a novel druggable target for therapeutic intervention.
2018-06-26 | GSE100483 | GEO
Project description:Breast cancer (BC) is the second most common type of cancer in women and one of the leading causes of cancer-related deaths worldwide. BC classification is based on the detection of three main histological markers: estrogen receptor alpha (ERα), progesterone receptor (PR) and the amplification of epidermal growth factor receptor 2 (HER2/neu). A specific BC subtype, named triple-negative BC (TNBC), lacks the aforementioned markers but a fraction of them express the estrogen receptor beta (ERβ). To investigate the functional role of ERβ in these tumors, interaction proteomics coupled to mass spectrometry (MS) was applied to deeply characterize the nuclear interactors partners in MDA-MD-468 and HCC1806 TNBC cells.
2019-12-03 | PXD014468 | Pride
Project description:Triple-Negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with poor prognosis due to its propensity to form metastases. Unfortunately, the current treatment options are limited to chemotherapy such that identification of actionable targets are needed. The receptor tyrosine kinase AXL plays a role in the tumor cell dissemination and its expression in TNBC correlates with poor patients? survival. Here, we explored whether exploiting an AXL knockdown gene signature in TNBC cells may offer an opportunity for drug repurposing. To this end, we queried the PharmacoGx pharmacogenomics platform with an AXL gene signature which revealed Phenothiazines, a class of Dopamine Receptors antagonists (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if drugs may be active to limit growth and metastatic progression of TNBC cells, similarly to AXL depletion. We found that the Phenothiazines were able to reduce cel l invasion, proliferation and viability, and also increased apoptosis of TNBC cells in vitro. Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, these drugs showed were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics are novel anti-tumor and anti-metastatic agents that could potentially be repurposed, in combination with standard chemotherapy, for use in TNBC.
2019-04-01 | GSE120268 | GEO
Project description:The PI3K pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ~15% of breast cancers with no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC owing largely to still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long non-coding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC, and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted pro-tumorigenic roles in TNBC, and that it governed a previously undescribed mTORC2-dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, we show that LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative mRNA regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth and we show that the LINC01133-PROTOR1/PRR5 pathway tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA-based theranostic in clinical TNBC management. We performed comparative gene expression profiling analyses using RNA-seq of triplicates of control 4T1 cells (harboring empty plasmid control) and 4T1 cell trioplicates expressing exogenous LINC01133.
2022-10-03 | GSE212004 | GEO
Project description:TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, whether and how TET1 exerts catalytic activity-independent functions in regulating bivalent genes is not well understood. Therefore, we mapped the TET1 interactome in mouse ESCs using a SILAC IP-MS proteomics approach.
2022-06-10 | PXD033587 | Pride
Project description:Breast cancer is a heterogeneous disease for which prognosis and treatment strategies are largely governed by the receptor status (estrogen, progesterone and Her2-neu) of the tumor cells. Gene expression profiling of whole breast tumors further stratifies breast cancer into several molecular subtypes which also co-segregate with the receptor status of the tumor cells. We postulated that cancer associated fibroblasts (CAFs) within the tumor stroma may exhibit subtype specific gene expression profiles and thus contribute to the biology of the disease in a subtype specific manner. Several studies have reported gene expression profile differences between CAFs and normal breast fibroblasts but in none of these studies were the results stratified based on tumor subtypes. To address whether gene expression in breast cancer associated fibroblasts varies between breast cancer subtypes, we compared the gene expression profiles of early passage primary CAFs isolated from twenty human breast cancer samples representing three main subtypes; seven ER+, seven triple negative (TNBC) and six Her2+. We observed significant expression differences between CAFs derived from Her2+ breast cancer and CAFs from TNBC and ER+ cancers, particularly in pathways associated with cytoskeleton and integrin signaling. In the case of Her2+ breast cancer, the signaling pathways found to be selectively up regulated in CAFs may contribute to the more invasive properties and unfavorable prognosis of Her2+ breast cancer. These data demonstrate that in addition to the distinct molecular profiles that characterize the neoplastic cells, CAF gene expression is also differentially regulated in distinct subtypes of breast cancer. We isolated CAFs from twenty primary breast cancer samples representing three main subtypes (ER+ (n=7), TNBC (n=7), Her2+ (n=6)) and performed gene expression profile analyses on RNA isolated from these early passage CAFs. Those samples were done in two batches with 4 samples repeated in both batches. One TNBC sample was found to be an outlier and not used in the analysis.
2013-12-20 | E-GEOD-37614 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide negative selection CRISPR/Cas9 screen with PI3K and AKT inhibitors to identify targetable synthetic lethalities in TNBC. We found that cholesterol homeostasis is a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived organoids of estrogen receptor (ER)-negative breast cancer. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBCs show dysregulated SREBP-2 activation in response to single agent or combination AKT inhibitor and pitavastatin, and this was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss promoted lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. This work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.
2024-01-14 | GSE252944 | GEO
Project description:Triple negative breast cancer is an aggressive type of breast cancer with very little treatment options. TNBC is very heterogeneous with large alterations in the genomic, transcriptomic, and proteomic landscapes leading to various subtypes with differing responses to therapeutic treatments. We applied a multi-omics data integration method to evaluate the correlation of important regulatory features in TNBC BRCA1 wild-type MDA-MB-231 and TNBC BRCA1 5382insC mutated HCC1937 cells compared with normal epithelial breast MCF10A cells. The data includes DNA methylation, RNAseq, protein, phosphoproteomics, and histone post-translational modification. Data integration methods identified regulatory features from each omics method had greater than 80% positive correlation within each TNBC subtype. Key regulatory features at each omics level were identified distinguishing the three cell lines and were involved in important cancer related pathways such as TGFbeta signaling, PI3K/AKT/mTOR, and Wnt/beta-catenin signaling.
2021-06-24 | PXD025238 | Pride