Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 43, Pages 11494-11499Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1618091114
Keywords
Twist1; breast cancer; EMT; metastasis; mouse model
Categories
Funding
- NIH [P30CA125123, CA112403, CA193455, CA204926]
- Cancer Prevention and Research Institute of Texas [RP120732-P5, RP150197]
- National Natural Science Foundation of China [81572619, 81472482]
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Twist1 is an epithelial-mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1(TKO)). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in similar to 6% of the advanced WT tumor cells. Most of these Twist1(+) cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ER alpha and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin(+)/vimentin(+)). In advanced Twist1(TKO) tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1(TKO) tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1(TKO) tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis.
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