Abstract
BackgroundEpithelial-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.MethodsmRNA 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.ResultsUtilizing 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).ConclusionsThe 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.
Highlights
Epithelial-to-mesenchymal transition (EMT) is a complex and dynamic process that involves transdifferentiation of the cells by means of changes in the cell state
We studied epithelial–mesenchymal transition status, as assessed by gene expression profiling, for 151 primary invasive breast carcinomas of patients whom all developed metastatic disease
The designated EMT status has been correlated to the metastatic behavior and survival outcomes
Summary
Epithelial-to-mesenchymal transition (EMT) is a complex and dynamic process that involves transdifferentiation of the cells by means of changes in the cell state. EMT is initiated with the activation of transcription factors such as Snail, Twist, Slug, and Zeb and is regulated by the modulation of multiple epigenetic regulatory mechanisms [43, 48] This process results in the loss of epithelial features and acquiring mesenchymal properties such as motility, invasiveness, and resistance to apoptosis, eventually leading to colonization and metastasis formation [40]. During the process of tumor progression, these cells were shown to gain CK14 expression especially at the invasive edges of the organoids With these results, the authors have demonstrated the potential role of Snail and subsequent EMT activation in obtaining basal features usually seen in more aggressive breast tumor types [59]. The association between EMT status of the primary tumors and their pattern of metastatic disease and the possibility of determining this EMT status with the help of selected routine immunohistochemical stains was investigated
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