Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signaling networks and conserved oncogenic pathways

Ali, Naveid A.; Jianmin Wu; Hochgräfe, Falko; Chan, Howard; Nair, Radhika; Ye, Sunny; Luxi Zhang; Lyons, Ruth J.; Pinese, Mark; Hong Ching Lee; Armstrong, Nicola; Ormandy, Christopher J.; Clark, Susan J.; Swarbrick, Alexander; Daly, Roger J.
October 2014
Breast Cancer Research;2014, Vol. 16 Issue 5, p1
Academic Journal
Introduction Although aberrant tyrosine kinase signaling characterizes particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken. This may identify conserved oncogenic pathways and potential therapeutic targets. Methods We applied an immunoaffinity/mass spectrometry workflow to three mouse models; murine stem cell virus (MSCV)-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus (MMTV)- polyoma virus middle-T-antigen (PyMT) (PyMT); and the p53 -/- transplant model (p53). Pathways and protein-protein interaction networks were identified by bioinformatics. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterized by Western blotting and array comparative genomic hybridization. The functional role of Mesenchymal epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering (si)RNA-mediated knockdown and cell proliferation assays. Results The three models could be distinguished based on tyrosine phosphorylation signatures and signaling networks. HER2 tumours exhibited a protein-protein interaction network centred on avian erythroblastic leukemia viral oncogene homolog 2 (Erbb2), epidermal growth factor receptor (Egfr) and platelet-derived growth factor receptor alpha (PDGFRa) and displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1 (Errfi1). In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol-3-kinase signaling pathway, whilst p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton, and shared signaling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, and Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were re-capitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2. Conclusion This study provides network-level insights into signaling in these breast cancer models and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signaling pathways. The Met-amplified, p53-null tumours provide a new pre-clinical model for a subset of triple-negative breast cancers.


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