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Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by
accelerating Twist1 degradation
#MMPMID25892968
Ma G
; He J
; Yu Y
; Xu Y
; Yu X
; Martinez J
; Lonard DM
; Xu J
Int J Biol Sci
2015[]; 11
(5
): 618-28
PMID25892968
show ga
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.
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