Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.

Abstract

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.

• Authors: Karsten Krug, Eric J Jaehnig, Shankha Satpathy, Lili Blumenberg, Alla Karpova, Meenakshi Anurag, George Miles, Philipp Mertins, Yifat Geffen, Lauren C Tang, David I Heiman, Song Cao, Yosef E Maruvka, Jonathan T Lei, Chen Huang, Ramani B Kothadia, Antonio Colaprico, Chet Birger, Jarey Wang, Yongchao Dou, Bo Wen, Zhiao Shi, Yuxing Liao, Maciej Wiznerowicz, Matthew A Wyczalkowski, Xi Steven Chen, Jacob J Kennedy, Amanda G Paulovich, Mathangi Thiagarajan, Christopher R Kinsinger, Tara Hiltke, Emily S Boja, Mehdi Mesri, Ana I Robles, Henry Rodriguez, Thomas F Westbrook, Li Ding, Gad Getz, Karl R Clauser, David Fenyö, Kelly V Ruggles, Bing Zhang, D R Mani, Steven A Carr, Matthew J Ellis, Michael A Gillette, Clinical Proteomic Tumor Analysis Consortium
• Journal: Cell (Cell) Vol. 183 Issue 5 Pg. 1436-1456.e31 (11 25 2020) ISSN: 1097-4172 [Electronic] United States
• PMID: 33212010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Retinoblastoma Protein
• Protein Kinases
• ERBB2 protein, human
• Receptor, ErbB-2
• APOBEC Deaminases

Topics

• APOBEC Deaminases (metabolism)
• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms (genetics, immunology, pathology, therapy)
• Carcinogenesis (genetics, pathology)
• Cohort Studies
• DNA Damage
• DNA Repair
• Female
• Humans
• Immunotherapy
• Metabolomics
• Middle Aged
• Molecular Targeted Therapy
• Mutagenesis (genetics)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Proteogenomics
• Receptor, ErbB-2 (metabolism)
• Retinoblastoma Protein (metabolism)
• Tumor Microenvironment (immunology)