Cell
Volume 183, Issue 5, 25 November 2020, Pages 1436-1456.e31
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Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

https://doi.org/10.1016/j.cell.2020.10.036Get rights and content
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Highlights

  • Comprehensive proteogenomics resource from prospectively collected breast tumors

  • Proteogenomics defines ERBB2 and Rb status with clinical implications

  • Acetylproteome profiling yields insights into subtype-specific cancer metabolism

  • Immune profiling nominates subsets of luminal tumors for immune therapy

Summary

The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this “proteogenomics” approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.

Keywords

CPTAC
proteogenomics
breast cancer
genomics
proteomics
phosphoproteomics
acetylation
mass spectrometry
immune checkpoint therapy
CDK 4/6 inhibitors

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17

These authors contributed equally

18

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