Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways
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Xinyan Wu1,2,*, Muhammad Saddiq Zahari1,2,*, Binyun Ma6, Ren Liu6, Santosh Renuse1,2,5, Nandini A. Sahasrabuddhe1,2,5, Lily Chen3, Raghothama Chaerkady1,2, Min-Sik Kim1,2, Jun Zhong1,2, Christine Jelinek1,2, Mustafa A. Barbhuiya1,2,5, Pamela Leal-Rojas1,2,7, Yi Yang1,2, Manoj Kumar Kashyap1,2,5, Arivusudar Marimuthu1,2,5, Min Ling1, Mary Jo Fackler3, Vanessa Merino3, Zhen Zhang3, Cynthia A. Zahnow3, Edward Gabrielson3,4, Vered Stearns3, Juan Carlos Roa8, Saraswati Sukumar3, Parkash S. Gill6, Akhilesh Pandey1,2,3,4
1Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, USA
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
3Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA
4Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA
5Institute of Bioinformatics, International Technology Park, Bangalore, India
6Department of Medicine, University of Southern California, Los Angeles, USA
7Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
8Advanced Center for Chronic Diseases (ACCDiS), Department of Pathology Pontificia Universidad Católica de Chile, Santiago, Chile
*These authors have contributed equally to this work
Akhilesh Pandey, e-mail: firstname.lastname@example.org
Keywords: triple negative breast cancer, protein phosphorylation, kinase, AXL, proteomics
Received: March 25, 2015 Accepted: August 24, 2015 Published: September 03, 2015
Breast cancer is the most prevalent cancer in women worldwide. About 15–20% of all breast cancers are triple negative breast cancer (TNBC) and are often highly aggressive when compared to other subtypes of breast cancers. To better characterize the biology that underlies the TNBC phenotype, we profiled the phosphotyrosine proteome of a panel of twenty-six TNBC cell lines using quantitative high resolution Fourier transform mass spectrometry. A heterogeneous pattern of tyrosine kinase activation was observed based on 1,789 tyrosine-phosphorylated peptides identified from 969 proteins. One of the tyrosine kinases, AXL, was found to be activated in a majority of aggressive TNBC cell lines and was accompanied by a higher level of AXL expression. High levels of AXL expression are correlated with a significant decrease in patient survival. Treatment of cells bearing activated AXL with a humanized AXL antibody inhibited cell proliferation and migration in vitro, and tumor growth in mice. Overall, our global phosphoproteomic analysis provided new insights into the heterogeneity in the activation status of tyrosine kinase pathways in TNBCs. Our approach presents an effective means of identifying important novel biomarkers and targets for therapy such as AXL in TNBC.
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