Forkhead box protein A1 confers resistance to transforming growth factor--induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation

Transforming growth factor- (TGF-) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF--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--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- 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--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--mediated signal transduction.