Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis
| Autor: | Qing Cheng, Kwong Y. Tsang, Jeffrey Schlom, Patrizia Ferroni, Bruce Huang, Antonella Spila, Romaine I. Fernando, H. Kim Lyerly, Francesco Cavaliere, Fiorella Guadagni, Claudia Palena, Mario Roselli, Leopoldo Costarelli, Mary T. Litzinger, Caroline Jochems, Duane H. Hamilton |
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| Rok vydání: | 2014 |
| Předmět: |
Oncology
Adult Fetal Proteins Cancer Research medicine.medical_specialty Brachyury Epithelial-Mesenchymal Transition Tissue Fixation Settore MED/06 - Oncologia Medica Messenger Vimentin Breast Neoplasms Cell Line Breast cancer Neoplasm Invasiveness Paraffin Embedding Humans Prognosis Aged Formaldehyde Cell Line Tumor T-Box Domain Proteins RNA Messenger Aged 80 and over Middle Aged Immunohistochemistry Female Internal medicine 80 and over medicine Carcinoma Epithelial–mesenchymal transition Tumor biology Mesenchymal stem cell medicine.disease Tumor progression biology.protein RNA Breast carcinoma |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1460-2105 |
| Popis: | The epithelial–mesenchymal transition (EMT) is a normal developmental process that allows the conversion of epithelial, polarized, and stationary cells into highly motile and invasive mesenchymal cells, a phenomenon required for the normal formation of the embryo (1,2). Recent investigations have demonstrated that a similar phenotypic switch can aberrantly take place during tumor progression, allowing epithelial cancer cells to lose cell polarity, epithelial markers, and cell-to-cell contacts, while simultaneously acquiring mesenchymal-associated markers, cell motility, and invasiveness (3,4). As a result, carcinoma cells undergoing EMT are enabled to initiate the cascade of events leading to the establishment of distant metastases (5). In breast cancer, the phenomenon of EMT has been shown to take place in highly aggressive tumors with a basal-like phenotype, which frequently show overexpression of mesenchymal proteins, including vimentin and smooth-muscle-actin, and cadherin switching (reduced E-cadherin and overexpression of N-cadherin) (6,7). In breast cancer patients undergoing neoadjuvant therapy, moreover, it has been shown that recurring tumors after treatment with standard anthracycline-taxane chemotherapy had an increased proportion of cells expressing EMT-associated genes, thus highlighting the importance of EMT in therapeutic resistance (8). We have identified brachyury, an embryonic transcription factor of the T-box family (9,10), as a driver of EMT in human carcinomas (11,12). High levels of brachyury expression in epithelial tumor cells have been shown to drive the acquisition of mesenchymal features in vitro, including motility and invasiveness, and to favor metastatic dissemination of tumor cells in vivo (11,12). In a recent study conducted with a monoclonal murine antibody, expression of brachyury protein was found in approximately 40% of non–small cell lung carcinomas and not in a range of human adult normal tissues, with the exception of low levels observed in testis and selected thyroid samples (13,14). We have been able to demonstrate the generation of brachyury-specific T cells capable of lysing human lung carcinoma cells (13). A phase I study is ongoing using a brachyury-based vaccine in patients with metastatic tumors (15). In this study we characterize the expression of brachyury in a range of malignant and benign breast tissues both at the mRNA and protein levels and present data on the potential role of brachyury in the biology of breast cancer. We also demonstrate the ability of brachyury-specific T cells to lyse human breast carcinoma cells, providing the rationale for the use of a brachyury-specific vaccine as a monotherapy or in combination therapy approaches for breast carcinoma. |
| Databáze: | OpenAIRE |
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