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Updated: Oct 14, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes
Brian D Lehmann1,2, Antonio Colaprico3,4, Tiago C Silva3
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. brian.d.lehmann@vumc.org.
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.
Insights
Triple-negative breast cancer (TNBC) subtypes have distinct genomic landscapes. Targeting polycomb repressor complex 2 (PRC2) can restore immune response and improve chemotherapy in mesenchymal TNBC.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Triple-negative breast cancer (TNBC) is a heterogeneous disease with distinct subtypes.
- Understanding the genomic and immune landscape of TNBC subtypes is crucial for developing targeted therapies.
Purpose of the Study:
- To comprehensively analyze the genomic landscape of TNBC subtypes.
- To identify subtype-specific vulnerabilities and potential therapeutic targets.
Main Methods:
- Multi-omic analysis including mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic data.
- Investigation of immune cell composition and PD-L1 expression.
- Functional studies involving pharmacological inhibition of PRC2 in murine tumor models.
Main Results:
- Mesenchymal TNBC tumors exhibit high mutation loads, genomic instability, lack of immune cells, and suppressed antigen presentation genes.
- Polycomb repressor complex 2 (PRC2) mediates transcriptional suppression of MHC-I via H3K27me3 modifications.
- Pharmacological inhibition of PRC2 (EZH2 or EED) restored MHC-I expression and enhanced chemotherapy efficacy in mesenchymal TNBC models.
Conclusions:
- PRC2 inhibition represents a promising therapeutic strategy for PD-L1 negative mesenchymal TNBC.
- Subtype-specific vulnerabilities offer opportunities for developing tailored treatment strategies for TNBC.
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