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

Authors

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

Date of this Version

12-1-2021

Document Type

Article

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.

DOI

10.1038/s41467-021-26502-6

Recommended Citation

Lehmann, Brian D.; Colaprico, Antonio; Silva, Tiago C.; Chen, Jianjiao; An, Hanbing; Ban, Yuguang; Huang, Hanchen; Wang, Lily; James, Jamaal L.; Balko, Justin M.; Gonzalez-Ericsson, Paula I.; Sanders, Melinda E.; Zhang, Bing; Pietenpol, Jennifer A.; and Chen, X. Steven, "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes" (2021). All Faculty. 252.
https://digitalcommons.fiu.edu/all_faculty/252