TY - JOUR
T1 - Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways
AU - Wu, Xinyan
AU - Zahari, Muhammad Saddiq
AU - Ma, Binyun
AU - Liu, Ren
AU - Renuse, Santosh
AU - Sahasrabuddhe, Nandini A.
AU - Chen, Lily
AU - Chaerkady, Raghothama
AU - Kim, Min Sik
AU - Zhong, Jun
AU - Jelinek, Christine
AU - Barbhuiya, Mustafa A.
AU - Leal-Rojas, Pamela
AU - Yang, Yi
AU - Kashyap, Manoj Kumar
AU - Marimuthu, Arivusudar
AU - Ling, Min
AU - Fackler, Mary Jo
AU - Merino, Vanessa
AU - Zhang, Zhen
AU - Zahnow, Cynthia A.
AU - Gabrielson, Edward
AU - Stearns, Vered
AU - Roa, Juan Carlos
AU - Sukumar, Saraswati
AU - Gill, Parkash S.
AU - Pandey, Akhilesh
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - AXL
KW - Kinase
KW - Protein phosphorylation
KW - Proteomics
KW - Triple negative breast cancer
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U2 - 10.18632/oncotarget.5020
DO - 10.18632/oncotarget.5020
M3 - Article
C2 - 26356563
AN - SCOPUS:84945161731
SN - 1949-2553
VL - 6
SP - 29143
EP - 29160
JO - Oncotarget
JF - Oncotarget
IS - 30
ER -