ATF6α inhibits ΔNp63α expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling

Endoplasmic reticulum (ER) stress is increasingly recognized as a driver of cancer progression; however, the precise molecular mechanisms by which ER stress facilitates tumor metastasis remain incompletely understood. In this study, we demonstrate that ER stress-activated ATF6α promotes breast cancer cell migration and metastasis by downregulating the expression of ΔNp63α, a key metastasis suppressor. Mechanistically, ATF6α reduces ΔNp63α expression through GRP78, which interacts with and activates AKT1. Activated AKT1 subsequently phosphorylates FOXO3a, leading to its degradation. Since FOXO3a directly transactivates ΔNp63α expression, its degradation results in reduced ΔNp63α levels. Furthermore, pharmacological inhibition or genetic knockdown of AKT1 upregulates ΔNp63α in vitro and suppresses tumor metastasis in vivo. Clinical analyses reveal that TP63 and FOXO3a expression are significantly reduced in breast cancer tissues compared to normal tissues, whereas ATF6 and GRP78 expression are elevated. Moreover, low TP63 and high GRP78 expression are associated with a poor prognosis in breast cancer patients. Collectively, these findings elucidate the pivotal role of the ATF6α-GRP78-AKT1-FOXO3a axis in chronic ER stress-mediated downregulation of ΔNp63α, establishing a molecular framework for targeting this pathway as a potential therapeutic strategy against breast cancer metastasis.