Forkhead box protein A1 confers resistance to transforming growth factor-ß-induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation.
J Cell Biochem
; 120(2): 2259-2270, 2019 Feb.
Article
em En
| MEDLINE
| ID: mdl-30206966
ABSTRACT
Transforming growth factor-ß (TGF-ß) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF-ß-induced apoptosis, the molecular mechanisms underlying this resistance are largely unknown. Here, we show that forkhead box protein A1 (FOXA1), which is known as a pioneer transcription factor, suppresses TGF-ß-induced apoptosis of estrogen receptor-positive breast cancer cells. FOXA1 is found to inhibit nuclear translocation of Smad3, a key transcription factor downstream of TGF-ß signaling, through suppression of the binding of Smad3 to the nuclear import receptor importin7. Furthermore, RNA sequencing analyses show that knockdown of FOXA1 upregulates Smad3-mediated proapoptotic gene expression. These results demonstrate that FOXA1 as a potent survival factor that suppresses TGF-ß-induced apoptosis by inhibiting Smad3 signaling in estrogen receptor-positive breast cancer cells. Thus, we provide evidence for the first time that FOXA1 localizing to the cytoplasm negatively regulates Smad3-induced apoptosis in TGF-ß-mediated signal transduction.
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MEDLINE
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En
Ano de publicação:
2019
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Article