Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Clinical Proteomic Tumor Analysis Consortium

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1436-1456.e31
JournalCell
Volume183
Issue number5
DOIs
StatePublished - Nov 25 2020

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium through grants U24CA160034 (to S.A.C.), U24CA210986 (to S.A.C. and M.A.G.), U01CA214125 (to M.J.E. and S.A.C.), U24CA210979 (to D.R.M. and G.G.), U24CA210954 (to B.Z.), and U24CA210972 (to L.D. and D.F.) and by NIH grant T32CA203690 (to J.T.L.). M.J.E. is a Susan G. Komen Foundation Scholar, a McNair Scholar supported by the McNair Medical Institute at The Robert and Janice McNair Foundation, and a recipient of a CPRIT (Cancer Prevention and Research Institute of Texas) Established Investigator Award (RR140027). Conception and Design, K.K. S.S. P.M. L.C.T. K.R.C. D.R.M. S.A.C. M.J.E. and M.A.G.; Experiment or Data Collection, S.S. G.M. P.M. and L.C.T.; Computation and Statistical Analysis, K.K. E.J.J. S.S. L.B. A.K. M.A. Y.G. D.I.H. S.C. Y.E.M. J.T.L. C.H. R.B.K. A.C. M.A.W. K.R.C. K.V.R. and D.R.M.; Writing – Original Draft, K.K. E.J.J. S.S. L.B. A.K. M.A. S.A.C. M.J.E. and M.A.G.; Supervision, S.S. C.B. T.F.W. L.D. G.G. D.F. K.V.R. B.Z. D.R.M. S.A.C. M.J.E. and M.A.G.; Administration, C.R.K. T.H. E.S.B. M.M. A.I.R. and H.R. All authors contributed to data interpretation and review and editing of the manuscript. M.J.E reports ownership and royalties associated with Bioclassifier LLC through sales by Nanostring LLC and Veracyte for the “Prosigna” breast cancer prognostic test. He also reports ad hoc consulting for AstraZeneca, Foundation Medicine, G1 Therapeutics, Novartis, Sermonix, Abbvie, Lilly and Pfizer. B.Z. has received research funding from Bristol-Myers Squibb. S.A.C. is a scientific advisory board member of Kymera, PTM BioLabs, and Seer and ad hoc consultant to Pfizer and Biogen.

Funding Information:
This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium through grants U24CA160034 (to S.A.C.), U24CA210986 (to S.A.C. and M.A.G.), U01CA214125 (to M.J.E. and S.A.C.), U24CA210979 (to D.R.M. and G.G.), U24CA210954 (to B.Z.), and U24CA210972 (to L.D. and D.F.) and by NIH grant T32CA203690 (to J.T.L.). M.J.E. is a Susan G. Komen Foundation Scholar, a McNair Scholar supported by the McNair Medical Institute at The Robert and Janice McNair Foundation , and a recipient of a CPRIT (Cancer Prevention and Research Institute of Texas) Established Investigator Award ( RR140027 ).

Funding Information:
M.J.E reports ownership and royalties associated with Bioclassifier LLC through sales by Nanostring LLC and Veracyte for the “Prosigna” breast cancer prognostic test. He also reports ad hoc consulting for AstraZeneca, Foundation Medicine, G1 Therapeutics, Novartis, Sermonix, Abbvie, Lilly and Pfizer. B.Z. has received research funding from Bristol-Myers Squibb. S.A.C. is a scientific advisory board member of Kymera, PTM BioLabs, and Seer and ad hoc consultant to Pfizer and Biogen.

Publisher Copyright:
© 2020 The Authors

Keywords

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

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