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Catechol-O-methyl transferase suppresses cell invasion and interplays with MET signaling in estrogen dependent breast cancer

ABSTRACT: Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer (BC) cells. To delineate COMT role in metastasis of estrogen receptor (ER) dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A BC model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). We performed comparative gene expression analysis using data obtained from RNA-seq of COMT-overexpressing and control cells in biological duplicates.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203435 | GEO | 2023/02/01

REPOSITORIES: GEO

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Catechol-O-methyl transferase suppresses cell invasion and interplays with MET signaling in estrogen dependent breast cancer

Project description:Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer cells. To delineate COMT role in metastasis of estrogen receptor dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A breast cancer model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). This PRIDE project includes quantitative analysis results for the total proteome LC-DIA-MS/MS experiment evaluating COMT overexpression in MCF7 breast cancer cell line, and results of pulldown analysis of COMT-interacting proteins in MCF7 cells.

2023-01-31 | PXD033833 | Pride

Integrated multiplexed assays of variant effect reveal determinants of catechol-O-methyltransferase gene expression

Project description:Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase and decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped the cis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alter COMT expression. Finally, we trained machine learning models to map signatures of variant effects on COMT gene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants in COMT and highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression

2023-11-06 | GSE246139 | GEO

In-situ Click Reaction Coupled with Quantitative Proteomics for Identification of Protein Targets of Catechol Estrogens

Project description:Catechol estrogens (CEs) are metabolic electrophiles that actively undergo covalent interaction with cellular proteins, influencing molecular function. There is no feasible method to identify their binders in a living system. Herein, we developed a click chemistry-based approach using ethinylestradiol(EE2) as the precursor probe coupled with quantitative proteomics to identify protein targets of CEs and classify their binding strengths.

2022-02-28 | PXD009657 | Pride

Impaired locomotor behavior of C. elegans neuroligin mutants is dependent of the catechol-O-methyltransferase COMT-4

Project description:Neuroligins are neuronal membrane adhesion molecules that have been involved in neuro-psychiatric and neuro-developmental disorders. They interact with neurexins and other specific proteins in the synaptic cleft. The nlg-1 gene of Caenorhabditis elegans encodes NLG-1, an ortholog of human neuroligins. NLG-1 is involved in dopaminergic and serotoninergic signaling that controls the locomotory rate of the nematode. When well fed animals are transferred to a plate with food (bacterial lawn) they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, food deprived animals when moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR) is serotonin dependent. C. elegans nlg-1- deficient mutants are impaired in BSR, ESR and other locomotory behaviors such as gentle touch response. Here we report that nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme that presumably has catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants recovers wild type phenotypes of BSR, ESR and gentle touch responses. Based on these results we propose a model for the neuroligin function in modulating the dopamine-dependent locomotory behavior in the nematode.

2018-05-31 | GSE97980 | GEO

ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

Project description:ATM gene mutation carriers are predisposed to estrogen receptor (ER)-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis following ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. Following estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.

2023-06-01 | GSE218320 | GEO

Identification of Cytosolic Protein Targets of Catechol Estrogens in Breast Cancer Cells Using a Click Chemistry-based Workflow

Project description:Catechol estrogens (CEs) are known to be toxic metabolites and the initiators in the oncogenesis of breast cancers via forming covalent adducts with DNAs. CEs shall also react with proteins but their cellular protein targets remain un-explored. Here we reported the identification of protein targets of CEs in the soluble cytosol of estrogen-sensitive breast cancer cells by multiple comparative proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS) coupled with an improved click chemistry-based workflow. Multiple comparative proteomics composed of experimental pair (probe versus solvent) and two control pairs (solvent versus solvent and probe versus solvent without enrichment), were studied using stable isotope dimethyl labeling. The use of 4-hydroxyethynylestradiol (4OHEE2) probe with an amide-free linker coupled with on-bead digestion and re-digestion of the proteins cleaved from the beads was shown to greatly improve the recovery and identification of CEs-adducted peptides. A total of 310 protein targets and 35 adduction sites were repeatedly (n≥2) identified with D/H (probe/solvent) ratio >4 versus only one identified with D/H >4 from the two control pairs, suggesting that our workflow imposes only a very low background. Meanwhile, multiple comparative D/H ratios revealed that CEs may down-regulate many target proteins involved in the metabolism or detoxification, suggesting a negative correlation between CEs-induced adduction and expression of proteins acting on the alleviation of stress-induced cellular damages. The reported method and data shall provide opportunities to study the progression of estrogen metabolism-derived diseases and biomarkers.

2020-09-28 | PXD017731 | Pride

Proteomics identification and validation of desmocollin-1 and catechol-O-methyltransferase as proteins associated with breast cancer cell migration and metastasis

Project description:Biological treatment of many cancers currently targets membrane bound receptors located on a cell surface. To identify novel membrane proteins associated with migration and metastasis of breast cancer cells, we selected and characterized a more migrating subpopulation of MDA-MB-231 breast cancer cells. We applied quantitative mass spectrometry with SILAC labeling to analyze their surfaceome and compared it with that of paternal MDA-MB-231 cells. Among 818 identified proteins (FDR < 0.01), 124 differentially abundant cell surface proteins with at least one transmembrane domain were found. Of these, (i) catechol-O-methyltransferase (COMT) was successfully verified as a protein associated with lymph node metastasis of triple negative breast cancer as well as tumor grade by targeted data extraction from the SWATH-MS data set of 96 breast cancer tissues, and (ii) desmocollin-1 (DSC1) was verified as a protein connected with lymph node status of luminal A breast cancer, tumor grade and Her-2 receptor by immunohistochemistry in the same set of patients. Kaplan-Meier analysis associated COMT and DSC1 with decreased overall survival in breast cancer subsets. Our findings indicate importance of both proteins for breast cancer development and metastasis

2019-10-23 | PXD013162 | Pride

Gene Expression Data from Prefrontal Cortex and Nucleus Accumbens from Inbred Strains of Mice

Project description:Catechol-O-methyltransferase (COMT) is an ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity (Andersen & Skorpen, 2009) and risk for developing psychiatric disorders (Harrison & Tunbridge, 2008). A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation (Nackley et al., 2006). However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have pursued a genome-wide approach to examining gene expression in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed. This expression difference was validated with qPCR. A B2-B4 Short Interspersed Element (SINE) was inserted in the 3'UTR of Comt1 in 14 strains that also shared a common haplotype. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element demonstrate that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3'UTR B2-B4 SINE element, regulates Comt1 expression and mouse behavior.

2010-02-03 | GSE20160 | GEO

Gene expression profiling data following TRIM8 knockdown in MCF-7 cells

Project description:Breast cancer (BC) is the most common female malignancies worldwide, and 70% of cases are estrogen receptor α (ERα) positive. In this study, we report that the E3 ubiquitin ligase TRIM8 acts as a novel regulator of ER signaling. TRIM8 is downregulated in BC and is associated with poor prognosis. In addition, the protein level of TRIM8 is negatively correlated with ERα expression. To investigate whether TRIM8 mediated estrogen signaling pathway, we generated a knockdown model of TRIM8 in human MCF7 cells.

2020-08-29 | GSE157109 | GEO

Genome-wide characterization of the Fur regulatory network reveals a link between catechol degradation and bacillibactin metabolism in Bacillus subtilis

Project description:The goal of this study is to obtain a genomic view of the Fur regulatory network under both iron replete and iron deficient conditions in Bacillus subtilis using ChIP-seq. Besides the known Fur target sites, 70 putative DNA binding sites were identified, and the vast majority had higher occupancy under iron sufficient conditions. In addition,we discovered a role for catechol degradation in bacillibactin metabolism, and provided evidence that catechol 2,3-dioxygenase can detoxify endogenously produced catechol substrates in addition to its more widely studied role in biodegradation of environmental aromatic compounds and pollutants.

2018-08-29 | GSE119163 | GEO

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