Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 43; pp. 11494 - 11499
• Main Authors: Xu, Yixiang, Lee, Dong-Kee, Feng, Zhen, Xu, Yan, Bu, Wen, Li, Yi, Liao, Lan, Xu, Jianming
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.10.2017
• Subjects: Animal models; Biological Sciences; Breast cancer; Cancer; Cell migration; E-cadherin; Lungs; Mammary gland; Markers; Mesenchyme; Metastases; Metastasis; Mice; Plastic properties; Plasticity; Transcription factors; Tumor cells; Tumors; Vimentin; breast cancer; mouse model; metastasis; EMT; Twist1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1618091114

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 (Twist1TKO). 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 ∼6% of the advanced WT tumor cells. Most of these Twist1⁺ cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin⁺/vimentin⁺). In advanced Twist1TKO 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 Twist1TKO 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 Twist1TKO 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.