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

TLDR

Triple‑negative breast cancer comprises diverse subtypes with distinct transcriptional, biological, and immune profiles, including basal‑like, mesenchymal, and luminal androgen receptor variants, and these differences point to subtype‑specific therapeutic opportunities. The study performed an integrative multi‑omics analysis—mutation, copy‑number, transcriptomic, epigenetic, proteomic, and phospho‑proteomic profiling—to map the genomic landscape of TNBC subtypes. Mesenchymal TNBC tumors exhibit high mutation burden, genomic instability, immune‑cell paucity, low PD‑L1, hypomethylation, and suppressed antigen presentation via PRC2‑mediated H3K27me3; inhibiting PRC2 restores MHC‑I and improves chemotherapy response in mouse models, supporting PRC2 inhibitors for PD‑L1‑negative mesenchymal disease.

Abstract

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.