title: Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Muhammad Saddiq
authors.initials: MS
authors.lastname: Zahari
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Binyun
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Bioinformatics, International Technology Park, Bangalore, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Renuse
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Bioinformatics, International Technology Park, Bangalore, India.
authors.forename: Nandini A
authors.initials: NA
authors.lastname: Sahasrabuddhe
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Raghothama
authors.initials: R
authors.lastname: Chaerkady
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Min-Sik
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Jelinek
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Bioinformatics, International Technology Park, Bangalore, India.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Barbhuiya
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Leal-Rojas
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Bioinformatics, International Technology Park, Bangalore, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Kashyap
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Bioinformatics, International Technology Park, Bangalore, India.
authors.forename: Arivusudar
authors.initials: A
authors.lastname: Marimuthu
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ling
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Fackler
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Merino
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Department of Pathology Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Roa
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005583:Fourier Analysis; D006801:Humans; D053208:Kaplan-Meier Estimate; D013058:Mass Spectrometry; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010641:Phenotype; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: AXL; kinase; protein phosphorylation; proteomics; triple negative breast cancer