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.

G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance

“…3C–F). As previously reported36, we found that AXL mRNA levels were significantly increased in TNBC patients, compared to normal breast tissue (Fig. 2D, p = 0.033).…”

Therapeutic activity of DCC‐2036, a novel tyrosine kinase inhibitor, against triple‐negative breast cancer patient‐derived xenografts by targeting AXL/MET

“…As a novel third‐generation TKI, DCC‐2036 has a broader kinase inhibition profile than second‐generation TKIs, such as dasatinib, sorafenib and gefitinib. DCC‐2036 potently inhibits multitargets, including SRC, RAF, VEGFR2, AXL and MET, which are activated and/or highly expressed in multiple TNBC subtypes . Our study indicated that DCC‐2036 efficiently inhibits TNBC in vitro and in vivo .…”

“…Recently, tyrosine kinases (TKs) have been suggested to be potential actionable targets due to their activation and high expression in multiple TNBC subtypes . The success of Herceptin (trastuzumab) in HER2‐positive breast cancer underlines the promise of targeting TKs.…”

Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer

“…Several studies have reported that different major signalling networks are activated specifically in TNBC 14,109,112 . Phosphorylation of HMGA1 turned on the IL4-mediated signalling pathway and enhanced the metastatic potential of TNBC tumors 109 .…”

“…However substantial changes in key components of this pathway (such as AKT and PI3K) were not observed in breast cancer subtypes 14 , consistent with the particularly aggressive nature of TNBC. Wu et al used a SILAC based quantitative phosphoproteomic approach to assess tyrosine kinase activity in TNBC and discovered multiple activated kinase signalling pathways 112 . Their phosphoproteomic analysis showed that AXL, a receptor tyrosine kinase, was highly phosphorylated in TNBC.…”