The GATA3-RFPL3-ASK1 axis suppresses breast cancer growth and lung metastasis.

Despite the great improvements made in its clinical management during the past decades, breast cancer remains a challenge with considerably high morbidity and mortality. Further efforts to explore new biomarkers with promising clinical potential are still needed nowadays. Collectively, our findings reveal the GATA3-RFPL3-ASK1 axis as a novel tumor-suppressive pathway in breast cancer. Mechanistically, GATA3 transcriptionally activates RFPL3 by directly binding to its promoter. Subsequently, RFPL3 stabilizes and activates ASK1 via K63-linked polyubiquitination, which in turn activates the ASK1-JNK/p38 signaling cascade. The signaling cascade induces apoptosis. Concurrently, this signaling cascade inhibits epithelial-mesenchymal transition (EMT) and invadopodia formation, thereby effectively inhibiting cell migration and invasion. The GATA3-RFPL3-ASK1 axis suppresses breast cancer growth and lung metastasis in vivo.