Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
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This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA160034 (Broad Institute; Fred Hutchinson Cancer Research Center), U24CA160036 (Johns Hopkins University), U24CA160019 (Pacific Northwest National Laboratory), U24CA159988 (Vanderbilt University), U24CA160035 (Washington University, St. Louis; University of North Carolina, Chapel Hill). P.W. and F.P. were also supported by SUB-R01GM108711 and MJE by CPRIT grant RR140033. M.J.E. is also a McNair Foundation Scholar. D.F. was supported by Leidos contract 13XS068. Primary genomics data for this study were generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. Resequencing of select samples conducted in this study was supported by National Cancer Institute (NCI) CPTAC award U24CA160035. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov/. We also acknowledge the expert assistance of J. Snider, P. Erdmann-Gilmore and R. Connors for the preparation of the tumour tissues for solubilization. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, for the use of the Tissue Procurement Core, which provided accessioning, histologic processing and review for the TCGA samples included in this study. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842 (see more at http://www.siteman.wustl.edu/ContentPage.aspx?id=243#sthash.mEU0QuXx.dpuf). We also thank the HAMLET Core at The Washington University in St. Louis for providing breast cancer xenograft tumors. The HAMLET Core was supported in part by grants from NIH/NCRR Washington University-ICTS (UL1 RR024992) and Susan G. Komen for the Cure (KG 090422). F.M. was also supported by The Swedish Research Council (Dnr 2014-323). We also thank A. Subramanian, C. Flynn and J. Asiedu at the Broad Institute for their guidance and assistance in accessing LINCS to run a large number of enrichment queries.
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