Twist1 is a transcription factor driving epithelial-mesenchymal transition, 
invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 
knockout are embryonic lethal, while adult mice with inducible Twist1 knockout 
have no obvious health problems, suggesting that Twist1 is a viable therapeutic 
target for the inhibition of invasion and metastasis of breast cancer in adult 
patients. In this study, we expressed a luciferase protein or a 
Twist1-luciferase fusion protein in HeLa cells as part of a high throughput 
system to screen 1280 compounds in the Library of Pharmacologically Active 
Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein 
expression. One of the most interesting compounds identified is tamoxifen, a 
selective estrogen receptor (ER) modulator used to treat ER-positive breast 
cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in 
multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse 
mammary tumor cells with either ectopically or endogenously expressed Twist1. 
Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome 
inhibitor, suggesting that tamoxifen induces Twist1 degradation through the 
ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation 
was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated 
Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly 
inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of 
ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade 
and metastasize. These results indicate that tamoxifen can significantly 
accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, 
suggesting that tamoxifen can be used not only to treat ER-positive breast 
cancers but also to reduce Twist1-mediated invasion and metastasis in 
ER-negative breast cancers.