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

Brian D. Lehmann (), Antonio Colaprico, Tiago C. Silva, Jianjiao Chen, Hanbing An, Yuguang Ban, Hanchen Huang, Lily Wang, Jamaal L. James, Justin M. Balko, Paula I. Gonzalez-Ericsson, Melinda E. Sanders, Bing Zhang, Jennifer A. Pietenpol and X. Steven Chen ()
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Brian D. Lehmann: Vanderbilt University Medical Center
Antonio Colaprico: University of Miami Miller School of Medicine
Tiago C. Silva: University of Miami Miller School of Medicine
Jianjiao Chen: University of Miami Miller School of Medicine
Hanbing An: Vanderbilt University Medical Center
Yuguang Ban: University of Miami Miller School of Medicine
Hanchen Huang: University of Miami Miller School of Medicine
Lily Wang: University of Miami Miller School of Medicine
Jamaal L. James: Vanderbilt University Medical Center
Justin M. Balko: Vanderbilt University Medical Center
Paula I. Gonzalez-Ericsson: Vanderbilt University Medical Center
Melinda E. Sanders: Vanderbilt University Medical Center
Bing Zhang: Baylor College of Medicine
Jennifer A. Pietenpol: Vanderbilt University Medical Center
X. Steven Chen: University of Miami Miller School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

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.

Date: 2021
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DOI: 10.1038/s41467-021-26502-6

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