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Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases. METHODS: mRNA expression pro...

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Autores principales: Savci-Heijink, C. D., Halfwerk, H., Hooijer, G. K. J., Koster, J., Horlings, H. M., Meijer, S. L., van de Vijver, M. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438946/
https://www.ncbi.nlm.nih.gov/pubmed/30610490
http://dx.doi.org/10.1007/s10549-018-05089-5
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author Savci-Heijink, C. D.
Halfwerk, H.
Hooijer, G. K. J.
Koster, J.
Horlings, H. M.
Meijer, S. L.
van de Vijver, M. J.
author_facet Savci-Heijink, C. D.
Halfwerk, H.
Hooijer, G. K. J.
Koster, J.
Horlings, H. M.
Meijer, S. L.
van de Vijver, M. J.
author_sort Savci-Heijink, C. D.
collection PubMed
description BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases. METHODS: mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival. RESULTS: Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p < 0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively). CONCLUSIONS: The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10549-018-05089-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-64389462019-04-15 Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior Savci-Heijink, C. D. Halfwerk, H. Hooijer, G. K. J. Koster, J. Horlings, H. M. Meijer, S. L. van de Vijver, M. J. Breast Cancer Res Treat Preclinical Study BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases. METHODS: mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival. RESULTS: Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p < 0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively). CONCLUSIONS: The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10549-018-05089-5) contains supplementary material, which is available to authorized users. Springer US 2019-01-04 2019 /pmc/articles/PMC6438946/ /pubmed/30610490 http://dx.doi.org/10.1007/s10549-018-05089-5 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Preclinical Study
Savci-Heijink, C. D.
Halfwerk, H.
Hooijer, G. K. J.
Koster, J.
Horlings, H. M.
Meijer, S. L.
van de Vijver, M. J.
Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title_full Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title_fullStr Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title_full_unstemmed Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title_short Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
title_sort epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior
topic Preclinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438946/
https://www.ncbi.nlm.nih.gov/pubmed/30610490
http://dx.doi.org/10.1007/s10549-018-05089-5
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