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

Abstract

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.

Polyploid giant cancer cells, EZH2 and Myc upregulation in mammary epithelial cells infected with high-risk human cytomegalovirus

“…Our findings highlight the presence of a potential link between HCMV infection, Myc/EZH2 upregulation and polyploidy induction in vitro and in human breast cancer biopsies, supporting the proposed tumorigenesis properties of EZH2 and providing new prospect of using EZH2 inhibitors in the context of breast cancer. 95 A more detailed analysis of PRC2 target genes within CTH cells and their corresponding response to inhibitors may establish new avenues to understand the complex pathogenesis of breast cancer and open the door for targeted therapies in the future.…”

Rewiring of the Endocrine Network in Triple-Negative Breast Cancer

“…The accumulating evidence indicated that Erb, devoted to diminishing the genes encoding key components, positively related to TNBC aggressiveness. Moreover, the interplay of ERb and the intranuclear molecular chaperone instigates the process of gene regulation, RNA splicing, and chromatin remodeling at the transcriptional and posttranscriptional level, which was validated by the association between ERb and the polycomb repressor complexes 1 and 2 (PRC1/2) in the process of cholesterol biosynthesis inhibition in interaction proteomics (42,43).…”

CXCL14 Attenuates Triple-Negative Breast Cancer Progression by Regulating Immune Profiles of the Tumor Microenvironment in a T Cell-Dependent Manner

“…The NIH Integrative Data Platform (NIDAP, , accessed on 30 March 2022) was used to access and process TCGA breast cancer data from the Genomic Data Commons (GDC) data portal; HTseq counts were filtered for low-count and normalized with limma-voom and quantile normalization using R Bioconductor limma library v3.38.3. Molecular subtypes and TNBC classification of METABRIC and TCGA patients were adopted from Lehmann et al [ 42 ]. Correlation analysis and visualization were performed using R programming language v3.5.1 and ggplot2 R library v3.3.0.…”