Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways.
Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways.
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DOI：
10.18632/oncotarget.5020
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Pandey A
中科院分区：
文献类型：
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作者：
Wu X;Zahari MS;Ma B;Liu R;Renuse S;Sahasrabuddhe NA;Chen L;Chaerkady R;Kim MS;Zhong J;Jelinek C;Barbhuiya MA;Leal-Rojas P;Yang Y;Kashyap MK;Marimuthu A;Ling M;Fackler MJ;Merino V;Zhang Z;Zahnow CA;Gabrielson E;Stearns V;Roa JC;Sukumar S;Gill PS;Pandey A
乳腺癌是全世界女性中最常见的癌症。大约15%-20%的乳腺癌是三阴性乳腺癌(TNBC)，与其他类型的乳腺癌相比，通常具有很高的侵袭性。为了更好地表征TNBC表型背后的生物学特征，我们使用定量高分辨率傅立叶变换质谱仪分析了一组26个TNBC细胞系的磷酸酪氨酸蛋白质组。基于从969个蛋白质中鉴定出的1,789个酪氨酸磷酸化多肽，观察到了一种不同的酪氨酸激酶激活模式。研究发现，在大多数侵袭性的TNBC细胞系中，酪氨酸激酶AXL被激活，并伴随着AXL的高水平表达。Axl的高水平表达与患者存活率的显著降低相关。用人源化Axl抗体处理活化的Axl细胞，在体外抑制细胞的增殖和迁移，并抑制小鼠肿瘤的生长。总体而言，我们的全球磷酸蛋白质组学分析为TNBCs中酪氨酸激酶通路激活状态的异质性提供了新的见解。我们的方法提供了一种有效的方法来识别重要的新型生物标记物和治疗靶点，如TnBC中的Axl。
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.