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

Author

Listed:
  • Brian D. Lehmann

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Antonio Colaprico

    (University of Miami Miller School of Medicine
    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
    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
    University of Miami Miller School of Medicine)

  • Jamaal L. James

    (Vanderbilt University Medical Center)

  • Justin M. Balko

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Paula I. Gonzalez-Ericsson

    (Vanderbilt University Medical Center)

  • Melinda E. Sanders

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Bing Zhang

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jennifer A. Pietenpol

    (Vanderbilt University Medical Center
    Vanderbilt University)

  • X. Steven Chen

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

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.

Suggested Citation

  • 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 , 2021. "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26502-6
    DOI: 10.1038/s41467-021-26502-6
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