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Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes.

Nature communications | 2021

Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC.

Pubmed ID: 34725325 RIS Download

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This is a list of tools and resources that we have found mentioned in this publication.


ChIP-seq (tool)

RRID:SCR_001237

Set of software modules for performing common ChIP-seq data analysis tasks across the whole genome, including positional correlation analysis, peak detection, and genome partitioning into signal-rich and signal-poor regions. The tools are designed to be simple, fast and highly modular. Each program carries out a well defined data processing procedure that can potentially fit into a pipeline framework. ChIP-Seq is also freely available on a Web interface.

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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Reactome (tool)

RRID:SCR_003485

Collection of pathways and pathway annotations. The core unit of the Reactome data model is the reaction. Entities (nucleic acids, proteins, complexes and small molecules) participating in reactions form a network of biological interactions and are grouped into pathways (signaling, innate and acquired immune function, transcriptional regulation, translation, apoptosis and classical intermediary metabolism) . Provides website to navigate pathway knowledge and a suite of data analysis tools to support the pathway-based analysis of complex experimental and computational data sets.

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Cell Signaling Technology (tool)

RRID:SCR_004431

Privately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.

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STAR (tool)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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European Genome phenome Archive (tool)

RRID:SCR_004944

Web service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects. The repository allows you to explore datasets from numerous genotype experiments, supplied by a range of data providers. The EGA''s role is to provide secure access to the data that otherwise could not be distributed to the research community. The EGA contains exclusive data collected from individuals whose consent agreements authorize data release only for specific research use or to bona fide researchers. Strict protocols govern how information is managed, stored and distributed by the EGA project. As an example, only members of the EGA team are allowed to process data in a secure computing facility. Once processed, all data are encrypted for dissemination and the encryption keys are delivered offline. The EGA also supports data access only for the consortium members prior to publication.

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Bowtie (tool)

RRID:SCR_005476

Software ultrafast memory efficient tool for aligning sequencing reads. Bowtie is short read aligner.

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Synapse (tool)

RRID:SCR_006307

A cloud-based collaborative platform which co-locates data, code, and computing resources for analyzing genome-scale data and seamlessly integrates these services allowing scientists to share and analyze data together. Synapse consists of a web portal integrated with the R/Bioconductor statistical package and will be integrated with additional tools. The web portal is organized around the concept of a Project which is an environment where you can interact, share data, and analysis methods with a specific group of users or broadly across open collaborations. Projects provide an organizational structure to interact with data, code and analyses, and to track data provenance. A project can be created by anyone with a Synapse account and can be shared among all Synapse users or restricted to a specific team. Public data projects include the Synapse Commons Repository (SCR) (syn150935) and the metaGenomics project (syn275039). The SCR provides access to raw data and phenotypic information for publicly available genomic data sets, such as GEO and TCGA. The metaGenomics project provides standardized preprocessed data and precomputed analysis of the public SCR data.

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Bioconductor (tool)

RRID:SCR_006442

Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.

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EDASeq (tool)

RRID:SCR_006751

Software for numerical and graphical summaries of RNA-Seq read data. Within-lane normalization procedures to adjust for GC-content effect (or other gene-level effects) on read counts: loess robust local regression, global-scaling, and full-quantile normalization (Risso et al., 2011). Between-lane normalization procedures to adjust for distributional differences between lanes (e.g., sequencing depth): global-scaling and full-quantile normalization (Bullard et al., 2010).

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GenoList genome browser (tool)

RRID:SCR_007683

GenoList is a resource for microbial genomes. It provides links to databases that give information on specific microbes. A link to the Genolist itself also incorporates many microbial genomes and search and analysis tools. Of the links provided on the GenoList homepage, species included are: Bacillus subtilis Escherichia coli Mycobacterium tuberculosis Mycobacterium leprae Mycobacterium bovis Mycobacterium ulcerans Listeria monocytogenes Legionella pneumophila Helicobacter pylori Mycoplasma pulmonis Synechocystis Anabaena Staphylococcus aureus Streptococcus pneumoniae Streptococcus agalactiae Photorhabdus luminescens Candida albicans Bacillus subtilis Escherichia coli Mycobacterium tuberculosis Mycobacterium leprae Mycobacterium bovis Mycobacterium ulcerans Listeria monocytogenes Legionella pneumophila Helicobacter pylori Mycoplasma pulmonis Synechocystis Anabaena Staphylococcus aureus Streptococcus pneumoniae Streptococcus agalactiae Photorhabdus luminescens Candida albicans

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MuSiC (tool)

RRID:SCR_008792

A set of tools aimed at determining the significance of somatic mutations discovered within a given cohort of cancer samples, incorporating the cohort''s alignment data, variant lists and any relevant clinical data.

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Millipore (tool)

RRID:SCR_008983

An Antibody supplier

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LIMMA (tool)

RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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Genomics of Drug Sensitivity in Cancer (tool)

RRID:SCR_011956

A genomics database project is an academic research program to identify molecular features of cancers that predict response to anti-cancer drugs.

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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featureCounts (tool)

RRID:SCR_012919

A read summarization program, which counts mapped reads for the genomic features such as genes and exons.

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Abcam (tool)

RRID:SCR_012931

A commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.

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Genomic Data Commons Data Portal (GDC Data Portal) (tool)

RRID:SCR_014514

A unified data repository of the National Cancer Institute (NCI)'s Genomic Data Commons (GDC) that enables data sharing across cancer genomic studies in support of precision medicine. The GDC supports several cancer genome programs at the NCI Center for Cancer Genomics (CCG), including The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the Cancer Genome Characterization Initiative (CGCI). The GDC Data Portal provides a platform for efficiently querying and downloading high quality and complete data. The GDC also provides a GDC Data Transfer Tool and a GDC API for programmatic access.

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cBioPortal (tool)

RRID:SCR_014555

A portal that provides visualization, analysis and download of large-scale cancer genomics data sets.

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ggplot2 (tool)

RRID:SCR_014601

Open source software package for statistical programming language R to create plots based on grammar of graphics. Used for data visualization to break up graphs into semantic components such as scales and layers.

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GENCODE (tool)

RRID:SCR_014966

Human and mouse genome annotation project which aims to identify all gene features in the human genome using computational analysis, manual annotation, and experimental validation.

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ComplexHeatmap (tool)

RRID:SCR_017270

Software package to arrange multiple heatmaps and support various annotation graphics. Used to visualize associations between different sources of data sets and to reveal potential patterns.

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QuPath (tool)

RRID:SCR_018257

Open Source software package for digital pathology image analysis. Used for whole slide image analysis and digital pathology. Provides researchers with batch processing and scripting functionality, and extensible platform with which to develop and share new algorithms to analyze complex tissue images.

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BT-549 (tool)

RRID:CVCL_1092

Cell line BT-549 is a Cancer cell line with a species of origin Homo sapiens (Human)

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MDA-MB-468 (tool)

RRID:CVCL_0419

Cell line MDA-MB-468 is a Cancer cell line with a species of origin Homo sapiens (Human)

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Hs 578T (tool)

RRID:CVCL_0332

Cell line Hs 578T is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1806 (tool)

RRID:CVCL_1258

Cell line HCC1806 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1143 (tool)

RRID:CVCL_1245

Cell line HCC1143 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1937 (tool)

RRID:CVCL_0290

Cell line HCC1937 is a Cancer cell line with a species of origin Homo sapiens (Human)

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BALB/cAnNCrl (tool)

RRID:MGI:2683685

laboratory mouse with name BALB/cAnNCrl from MGI.

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