Twist1 Silences Foxa1 Expression to Promote Breast Cancer Progression
Abstract
Twist1 is a basic helix-loop-helix transcription factor family that serves as one of the master regulators promoting epithelial-mesenchymal transition (EMT). Twist1 has been shown in many studies to promote EMT, stemness, invasiveness and metastasis in multiple cancers, including breast cancer. However, the genetic role of Twist1 in spontaneous breast cancer has not been investigated, and it is also unknown whether Twist1 is required for cell invasion and metastasis of spontaneously developed cancer. In this study, using a new TVA/RCIP mouse model, we disrupted Twist1 in certain mammary luminal epithelial cells and specifically induced tumors from these cells. We found that tumor cell-specific knockout of Twist1 diminished lung metastasis without affecting primary tumor initiation or growth. The diminished lung metastasis is accompanied with the decreased EMT, angiogenesis and circulating tumor cells caused by Twist1 knockout. Twist1 expression was positively associated with late-stage tumors and negatively associated with ERα and Foxa1 expression in mouse tumors. We then identified Foxa1 as a novel direct target of Twist1 in human breast cancer. We further found that Twist1 inhibits Foxa1 expression through direct binding to its proximal promoter region and recruiting Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) transcriptional repressor complex in human breast cancer cells. Moreover, Twist1 also diminished transcriptional activator AP1 binding to Foxa1 promoter. Twist1 mediated Foxa1 down-regulation is essential for promoting breast cancer migration, invasion and metastasis. Restored Foxa1 expression significantly inhibits Twist1 dependent cell migration and invasion capability of MCF7 cells through inhibiting integrin α5, β1 and MMP9 expression. Importantly, Twist1^high Foxa1^low correlates with the poorest prognosis in breast cancer patients. These findings highlight Twist1 as a key player in promoting breast cancer progression to a more malignant phenotype and a potential therapeutic target.
Citation
Xu, Yixiang (2016). Twist1 Silences Foxa1 Expression to Promote Breast Cancer Progression. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /158963.