ARMCX3 Promotes Breast Cancer Progression by Suppressing the p-ERK–p53 Axis

Breast cancer remains a leading cause of cancer-related death among women, and ac-quired cisplatin resistance limits the efficacy of chemotherapy. Although ARMCX3 has been implicated in breast cancer progression, its underlying regulatory mechanisms remain unclear. Building on our previous findings that ARMCX3 knockdown suppresses malignant phenotypes and enhances cisplatin sensitivity, we investigated the down-stream mechanisms involved. Transcriptomic analysis revealed activation of the p53 signaling pathway following ARMCX3 depletion. Inhibition of p53 using PFT-α largely reversed the effects of ARMCX3 knockdown on proliferation, migration, invasion, cell-cycle arrest, and cisplatin sensitivity, identifying p53 as a critical mediator of ARMCX3 function. Further analysis demonstrated that ERK signaling contributes to p53 activation following ARMCX3 depletion. ARMCX3 knockdown impaired DNA damage repair, increased DNA damage accumulation, and enhanced cisplatin-induced apoptosis, while these effects were partially attenuated by inhibition of ERK or p53 signaling. Xenograft experiments further confirmed the involvement of p53 in ARMCX3 knock-down-mediated tumor suppression. Collectively, these findings identify the p-ERK–p53 axis as an important mechanism underlying ARMCX3-mediated regulation of breast cancer progression and cisplatin response, suggesting ARMCX3 as a potential thera-peutic target for improving chemotherapy efficacy.