Twist is a basic helix loop helix protein that plays a role both in development and in cancer biogenesis. While characterizing the effects of Twist on breast epithelial cell transformation, we identified E-cadherin as a target gene that is down-regulated by Twist. In this study, we demonstrate that Twist can transcriptionally repress E-cadherin in breast cancer cells. Using transient promoter assays, we show that Twist can down-regulate E-cadherin promoter activity by up to two folds. This is further supported by immunoblot analyses which indicated that over-expression of Twist can decrease E-cadherin protein levels in breast cancer cell lines. Subsequently, chromatin immunoprecipitation was performed on MCF-7/Twist and Hs578 T (high level of endogenous Twist expression), which confirmed Twist binding to the E-cadherin promoter. Finally, the functional relevance of this regulation was verified by quantitative real-time PCR and immunohistochemistry on a cohort of breast cancer samples.