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.
Highlights
Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition
TNBC patients were identified from TCGA13, CPTAC14, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)[15], and from the MET50016 using genomic data guided by the expression distribution of clinically defined estrogen receptor (ER), progesterone receptor (PR), and human epithelial growth factor receptor 2 (HER2) tumors (Supplementary Fig. 1a and “Methods”)
Blots are representative of two independent experiments. b Representative images show immunohistochemistry for major histocompatibility complex I (MHC-I) expression on individual cells in TNBC cell lines. c Histogram plots show the distribution of membrane-bound MHC-I protein (+) in TNBC models compared to unstained controls (−)
Summary
Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. 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. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC. TNBC subtypes are associated with different immune cell compositions; striking is the absence of immune cells in the mesenchymal subtype (M-subtype)[6] These data suggest mesenchymal TNBCs likely have developed mechanisms to escape immune surveillance. We show a comprehensive subtype-specific analysis of mutation, copy number, gene expression, DNA methylation, and proteomic data of TNBC patients in The Cancer Genome Atlas (TCGA)[13] and Clinical Proteomic Tumor Analysis Consortium (CPTAC)[14] that identifies a potential mechanism of immune escape and provides further understand the biology of TNBC subtypes. TNBC cell line and animal models identify genetic and pharmacological vulnerabilities and identify potential therapeutic strategies for TNBC patients
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