Molecular players in lymph node metastasis of low grade breast cancer: From proteomics-based target discovery to functional characterization
| Autoři | |
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| Rok publikování | 2012 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Popis | Target discovery phase of the project was focused on identification of proteins related to lymph node positivity (N1-2 vs. N0) in small (T1) low grade (G1) breast tumors in a set of 96 well characterized breast tumors designed according to grade, hormonal receptor status and lymph node status. The proteomic experiment was based on peptide labelling with isobaric tags for relative and absolute quantitation (iTRAQ) and their separation with two-dimensional liquid chromatography and tandem mass spectrometry (iTRAQ-2DLC-MS/MS). A set of 95 selected genes was then profiled also at transcript level. Spearman correlation based statistics revaled three gene clusters related to lymph node metastasis in low grade tumors, one of them exhibited partial co-expression with estrogene receptor cluster and one with urokinase plasminogen activator/inhibitor system related cluster. Set of proteins their expression changes were confirmed at both protein and transcript level was then validated using immunohistochemical tissue microarray analysis. Analysis of biomarker selectivity based on agreement between proteomics, transcriptomics and immunohistochemical data divided the potential biomarkers into two selectivity groups. For three very specific potential biomarkers, statistically significant correlation with patient survival was observed in a completely independent set of 53 patients. Our results indicate that molecular mechanisms of metastasis in low grade breast tumors involve specific proteolysis, strong activation of NF-kappaB pathway and changes in cytoskeletal and adhesive proteins, most of them in a manner differrent from high grade carcinomas. In an ongoing phase, functional characterization of the identified targets is focused on studying their role in cell migration, composition of cell surface proteins, protein-protein and functional interactions, and clinical validation. This work was supported by Czech Science Foundation (Project No. P304/10/0868) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). |
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