The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells.
Metastatic disease is responsible for the majority of human cancer deaths. Understanding the molecular mechanisms of metastasis is a major step in designing effective cancer therapeutics. Here we show that the T-box transcription factor Brachyury induces in tumor cells epithelial-mesenchymal transition (EMT), an important step in the progression of primary tumors toward metastasis. Overexpression of Brachyury in human carcinoma cells induced changes characteristic of EMT, including upregulation of mesenchymal markers, downregulation of epithelial markers, and an increase in cell migration and invasion. Brachyury overexpression also repressed E-cadherin transcription, an effect partially mediated by Slug. Conversely, inhibition of Brachyury resulted in downregulation of mesenchymal markers and loss of cell migration and invasion and diminished the ability of human tumor cells to form lung metastases in a xenograft model. Furthermore, we found Brachyury to be overexpressed in various human tumor tissues and tumor cell lines compared with normal tissues. We also determined that the percentage of human lung tumor tissues positive for Brachyury expression increased with the stage of the tumor, indicating a potential association between Brachyury and tumor progression. The selective expression of Brachyury in tumor cells and its role in EMT and cancer progression suggest that Brachyury may be an attractive target for antitumor therapies.
Fernando
Romaine I
RI
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Litzinger
Mary
M
Trono
Paola
P
Hamilton
Duane H
DH
Schlom
Jeffrey
J
Palena
Claudia
C
D015820:Cadherins / Q000235:genetics; D002455:Cell Division; D002465:Cell Movement; D018076:DNA, Complementary / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology; D005326:Fetal Proteins / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000473:pathology* / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D000098908:Brachyury Protein
D015820:Cadherins; D018076:DNA, Complementary; D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein