Abstract
Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. In a search for key regulators of metastasis in a murine breast tumor model, we have found that the transcription factor Twist, a master regulator of embryonic morphogenesis, plays an essential role in metastasis. Suppression of Twist expression in highly metastatic mammary carcinoma cells specifically inhibits their ability to metastasize from the mammary gland to the lung. Ectopic expression of Twist results in loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT). In human breast cancers, high level of Twist expression is correlated with invasive lobular carcinoma, a highly infiltrating tumor type associated with loss of E-cadherin expression. These results establish a mechanistic link between Twist, EMT, and tumor metastasis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cadherins / metabolism
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Carcinoma, Lobular / genetics
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Carcinoma, Lobular / metabolism
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Carcinoma, Lobular / pathology*
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Cell Line
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Cell Line, Tumor
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Cell Movement
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Luciferases / metabolism
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Lung Neoplasms / secondary
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology*
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Mesoderm
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Mice
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Mice, Inbred BALB C
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Morphogenesis
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Myogenic Regulatory Factors / antagonists & inhibitors*
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Neoplasm Transplantation
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism*
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Organ Size
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Repressor Proteins
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Transcription Factors / metabolism*
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Twist-Related Protein 1
Substances
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Cadherins
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FERD3L protein, human
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Myogenic Regulatory Factors
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Nuclear Proteins
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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TWIST1 protein, human
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Transcription Factors
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Twist-Related Protein 1
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Twist1 protein, mouse
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Luciferases