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A novel panel of proteins associated with lymph node metastasis in low-grade breast cancer

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BOUCHAL Pavel MARYÁŠ Josef GALOCZOVÁ Michaela FAKTOR Jakub DVOŘÁKOVÁ Monika THEODOROS Roumeliotis ZOUFALOVÁ Karolína ČÁPKOVÁ Lenka IMRICHOVÁ Hana BUDINSKÁ Eva GARBIS Spiros D. VOJTĚŠEK Bořivoj NENUTIL Rudolf

Rok publikování 2016
Druh Konferenční abstrakty
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
Popis Introduction: Current prognostic factors are insufficient for precise risk-discrimination in breast cancer patients with low grade breast tumors, which, in disagreement with theoretical prognosis, occasionally form early lymph node metastasis. We aimed to identify, clinically validate and functionally characterize potential markers suitable for predicting metastatic potential of these tumors. Methods: We employed iTRAQ-2DLC-MS/MS proteomics to 24 lymph node positive and 24 lymph node negative grade 1 luminal A primary breast tumors. Another group of 48 high-grade tumors (luminal B, triple negative, Her-2 subtypes) was also analyzed to investigate marker specificity for grade 1 luminal A tumors. From the total of 4405 proteins identified, the top 65 differentially expressed together with 30 previously identified and control markers were analyzed also at transcript level. Immunohistochemistry, gene expression analysis of an independent published dataset (N=343), and analysis of gene expression connection with survival of patients (N=1678) was performed. Association of these proteins with cell migration, invasiveness, epithelial-to-mesenchymal transition (EMT) and signaling pathways was also investigated in vitro. Results and conclusion: Increased levels of carboxypeptidase B1 (CPB1), PDZ and LIM domain protein 2 (PDLIM2) and ring finger protein 25 (RNF25) were associated specifically with lymph node positive grade 1 tumors, whereas stathmin 1 (STMN1) and thymosin beta 10 (TMSB10) associated with aggressive tumor phenotype also in high grade tumors at both protein and transcript level. For CPB1, these differences were also observed by immunohistochemical analysis on tissue microarrays. Upregulation of putative biomarkers in lymph node positive (vs. negative) luminal A tumors was validated by gene expression analysis for CPB1, PDLIM2 and a central transcription regulator of NF-kB pathway RELA. Moreover, statistically significant connections with patient survival were identified in another public dataset, confirming prognostic significance of CPB1 for node negative luminal A grade 1 breast tumors (p=0.025). Most of the proteins identified were associated with cell migration and invasiveness and moreover, PDLIM2 and STMN1 were connected with EMT. Our findings indicate unique pro-metastatic mechanisms in grade 1 tumors that include up-regulation of CPB1, activation of NF-?B pathway and changes in cell survival and cytoskeleton. These putative biomarkers have potential to identify the specific minor sub-population of breast cancer patients with low grade tumors who are at higher than expected risk of recurrence and who would benefit from more intensive follow-up and may require more personalized therapy. This work was supported by Czech Science Foundation (project No. 14-19250S), by the project MEYS – NPS I – LO1413 and by MH CZ - DRO (MMCI, 00209805).
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