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Combined proteomics and transcriptomics identifies carboxypeptidase B1 and nuclear factor KB (NF-KB) associated proteins as putative biomarkers of metastasis in low grade breast cancer

Combined proteomics and transcriptomics identifies carboxypeptidase B1 and nuclear factor KB (NF-KB) associated proteins as putative biomarkers of metastasis in low grade breast cancer
Combined proteomics and transcriptomics identifies carboxypeptidase B1 and nuclear factor KB (NF-KB) associated proteins as putative biomarkers of metastasis in low grade breast cancer
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. To identify markers for this group of patients, 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 (FDR < 5%), the top 65 differentially expressed together with 30 previously identified and control markers were analyzed also at transcript level. 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. Up-regulation of putative biomarkers in lymph node positive (versus negative) luminal A tumors was validated by gene expression analysis of an independent published data set (n = 343) for CPB1 (p = 0.00155), PDLIM2 (p = 0.02027) and RELA (p = 0.00015). Moreover, statistically significant connections with patient survival were identified in another public data set (n = 1678). Our findings indicate unique pro-metastatic mechanisms in grade 1 tumors that can 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 subpopulation 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.
1535-9476
1814-1830
Bouchal, P.
858de967-6994-44df-8b31-acd1e8999427
Dvorakova, M.
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Roumeliotis, T.
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Bortlicek, Z.
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Ihnatova, I.
17e43836-e63b-4ed6-80a2-6ff1ac7fd48b
Ho, J.T.
25a6f5c2-522f-4134-b687-ffcdedecdc02
Maryas, J.
4e34f268-69a3-4b23-8b29-375f587e6661
Imrichova, H.
df20a9f5-b30b-484b-9b37-e5da98d1b103
Budinska, E.
2a665a3d-0627-45d0-8679-0aa6c356cd94
Vyzula, R.
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Garbis, S.D.
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Vojtesek, B.
72fdb292-02f2-47b2-9eae-0fe256520bf4
Nenutil, R.
77b3603d-7076-4ae8-b539-2a6b2e6e4802
Bouchal, P.
858de967-6994-44df-8b31-acd1e8999427
Dvorakova, M.
fdb209f9-60fc-4b1b-8317-712c562e7221
Roumeliotis, T.
f4ae258d-23c9-4440-af44-15f572435fb2
Bortlicek, Z.
9d20d999-84c0-4eca-8f2a-eedfbfefb636
Ihnatova, I.
17e43836-e63b-4ed6-80a2-6ff1ac7fd48b
Ho, J.T.
25a6f5c2-522f-4134-b687-ffcdedecdc02
Maryas, J.
4e34f268-69a3-4b23-8b29-375f587e6661
Imrichova, H.
df20a9f5-b30b-484b-9b37-e5da98d1b103
Budinska, E.
2a665a3d-0627-45d0-8679-0aa6c356cd94
Vyzula, R.
79b5f075-6eb8-4785-9a5a-16c98b8c5caf
Garbis, S.D.
7067fd19-50c9-4d42-9611-f370289470bd
Vojtesek, B.
72fdb292-02f2-47b2-9eae-0fe256520bf4
Nenutil, R.
77b3603d-7076-4ae8-b539-2a6b2e6e4802

Bouchal, P., Dvorakova, M., Roumeliotis, T., Bortlicek, Z., Ihnatova, I., Ho, J.T., Maryas, J., Imrichova, H., Budinska, E., Vyzula, R., Garbis, S.D., Vojtesek, B. and Nenutil, R. (2015) Combined proteomics and transcriptomics identifies carboxypeptidase B1 and nuclear factor KB (NF-KB) associated proteins as putative biomarkers of metastasis in low grade breast cancer. Molecular & Cellular Proteomics, 14, 1814-1830. (doi:10.1074/mcp.M114.041335). (PMID:25903579)

Record type: Article

Abstract

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. To identify markers for this group of patients, 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 (FDR < 5%), the top 65 differentially expressed together with 30 previously identified and control markers were analyzed also at transcript level. 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. Up-regulation of putative biomarkers in lymph node positive (versus negative) luminal A tumors was validated by gene expression analysis of an independent published data set (n = 343) for CPB1 (p = 0.00155), PDLIM2 (p = 0.02027) and RELA (p = 0.00015). Moreover, statistically significant connections with patient survival were identified in another public data set (n = 1678). Our findings indicate unique pro-metastatic mechanisms in grade 1 tumors that can 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 subpopulation 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.

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Published date: 22 April 2015
Organisations: Cancer Sciences

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Local EPrints ID: 395381
URI: https://eprints.soton.ac.uk/id/eprint/395381
ISSN: 1535-9476
PURE UUID: e16e3fa5-b7ad-469a-b6b0-d637c9c73bd8

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Date deposited: 27 May 2016 13:40
Last modified: 17 Jul 2017 18:54

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Contributors

Author: P. Bouchal
Author: M. Dvorakova
Author: T. Roumeliotis
Author: Z. Bortlicek
Author: I. Ihnatova
Author: J.T. Ho
Author: J. Maryas
Author: H. Imrichova
Author: E. Budinska
Author: R. Vyzula
Author: S.D. Garbis
Author: B. Vojtesek
Author: R. Nenutil

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