ARMCX3 Regulates Breast Cancer Progression and Cisplatin Responsiveness Through p53-Related Signaling

Despite substantial advances in diagnosis and treatment, breast malignancy continues to cause considerable morbidity and mortality. Cisplatin has demonstrated therapeutic activity in selected patients with advanced breast cancer, but its clinical use may be limited by treatment resistance. Although ARMCX3 is implicated in other cancers, its role and underlying mechanisms in breast cancer remain unclear. We investigated ARMCX3 functions using depletion and rescue experiments, and ARMCX3 depletion reduced cell growth, migration, and invasion and increased cisplatin sensitivity in vitro, while re-expression rescued these phenotypes. Transcriptomic analysis revealed enrichment of the p53 pathway following ARMCX3 depletion. PFT-α treatment suppressed the protein level of p53 and attenuated the effects of ARMCX3 knockdown on cell proliferation, migration, invasion, cell-cycle arrest, and cisplatin response. ARMCX3 knockdown was also associated with altered DNA damage response signaling, enhanced cisplatin-induced apoptosis and suppressed tumor growth in vivo, and all these effects were attenuated by PFT-α treatment. These findings suggest that p53-associated signaling contributes to the effects of ARMCX3 depletion on breast cancer progression and cisplatin responsiveness. These results may help inform future studies exploring ARMCX3-associated signaling in the context of cisplatin response.