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

• Published in: Journal of cellular biochemistry 2019-02, Vol.120 (2), p.2259-2270
• Main Authors: Hirata, Kensuke, Takakura, Yuki, Shibazaki, Misato, Morii, Mariko, Honda, Takuya, Oshima, Motohiko, Aoyama, Kazumasa, Iwama, Atsushi, Nakayama, Yuji, Takano, Hiroyuki, Yamaguchi, Naoto, Yamaguchi, Noritaka
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast cancer; Cancer; Cytoplasm; Epithelial cells; Epithelium; Estrogens; Forkhead protein; Gene expression; Gene sequencing; Growth factors; importin7; Mammary gland; Molecular modelling; Nuclear transport; Proteins; Resistance factors; Ribonucleic acid; RNA; RNA transport; Signal transduction; Signaling; SMAD; Smad3 protein; Survival factor; TGF‐β; Transcription factors; Transforming growth factor; Transforming growth factor-b; Translocation
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27551

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. We found that the pioneer factor FOXA1 suppresses TGF‐β‐induced apoptosis in estrogen receptor–positive breast cancer cells. FOXA1 represses nuclear translocation of the transcription factor Smad3 through inhibition of its binding to importin7.