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2014 ; 145
(3
): 593-604
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor
panobinostat via inhibition of ZEB family of EMT master regulators
#MMPMID24810497
Rhodes LV
; Tate CR
; Segar HC
; Burks HE
; Phamduy TB
; Hoang V
; Elliott S
; Gilliam D
; Pounder FN
; Anbalagan M
; Chrisey DB
; Rowan BG
; Burow ME
; Collins-Burow BM
Breast Cancer Res Treat
2014[Jun]; 145
(3
): 593-604
PMID24810497
show ga
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype
that lacks effective targeted therapies. The epithelial-to-mesenchymal transition
(EMT) is a key contributor in the metastatic process. We previously showed the
pan-deacetylase inhibitor LBH589 induces CDH1 expression in TNBC cells,
suggesting regulation of EMT. The purpose of this study was to examine the
effects of LBH589 on the metastatic qualities of TNBC cells and the role of EMT
in this process. A panel of breast cancer cell lines (MCF-7, MDA-MB-231, and
BT-549), drugged with LBH589, was examined for changes in cell morphology,
migration, and invasion in vitro. The effect on in vivo metastasis was examined
using immunofluorescent staining of lung sections. EMT gene expression profiling
was used to determine LBH589-induced changes in TNBC cells. ZEB overexpression
studies were conducted to validate requirement of ZEB in LBH589-mediated
proliferation and tumorigenesis. Our results indicate a reversal of EMT by LBH589
as demonstrated by altered morphology and altered gene expression in TNBC. LBH589
was shown to be a more potent inhibitor of EMT than other HDAC inhibitors, SAHA
and TMP269. Additionally, we found that LBH589 inhibits metastasis of MDA-MB-231
cells in vivo. These effects of LBH589 were mediated in part by inhibition of
ZEB, as overexpression of ZEB1 or ZEB2 mitigated the effects of LBH589 on
MDA-MB-231 EMT-associated gene expression, migration, invasion, CDH1 expression,
and tumorigenesis. These data indicate therapeutic potential of LBH589 in
targeting EMT and metastasis of TNBC.