Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways

Xinyan Wu, Muhammad Saddiq Zahari, Binyun Ma, Ren Liu, Santosh Renuse, Nandini A. Sahasrabuddhe, Lily Chen, Raghothama Chaerkady, Min Sik Kim, Jun Zhong, Christine Jelinek, Mustafa A. Barbhuiya, Pamela Leal-Rojas, Yi Yang, Manoj Kumar Kashyap, Arivusudar Marimuthu, Min Ling, Mary Jo Fackler, Vanessa Merino, Zhen ZhangCynthia A. Zahnow, Edward Gabrielson, Vered Stearns, Juan Carlos Roa, Saraswati Sukumar, Parkash S. Gill, Akhilesh Pandey

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)29143-29160
Number of pages18
JournalOncotarget
Volume6
Issue number30
DOIs
StatePublished - 2015

Keywords

  • AXL
  • Kinase
  • Protein phosphorylation
  • Proteomics
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Wu, X., Zahari, M. S., Ma, B., Liu, R., Renuse, S., Sahasrabuddhe, N. A., Chen, L., Chaerkady, R., Kim, M. S., Zhong, J., Jelinek, C., Barbhuiya, M. A., Leal-Rojas, P., Yang, Y., Kashyap, M. K., Marimuthu, A., Ling, M., Fackler, M. J., Merino, V., ... Pandey, A. (2015). Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways. Oncotarget, 6(30), 29143-29160. https://doi.org/10.18632/oncotarget.5020