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