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ObjectiveThe role of the tumor suppressor p53 apoptosis effector related to PMP-22 (PERP) in breast cancer metastasis remains unclear. This study investigated PERP's role in metastatic progression, its clinical significance, and the mechanisms underlying its effects.MethodsPERP expression was assessed in breast cancer cell lines, public datasets, and 142 patient samples using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry. In vitro migration and invasion assays as well as in vivo metastasis model were performed after PERP overexpression or knockdown in MDA-MB-231 and MCF-7 cells. The roles of activating transcription factor 3 (ATF3) and heat shock protein family A member 6 (HSPA6) were evaluated through small-interfering RNA-mediated modulation, RNA sequencing, western blotting, RT-qPCR, and chromatin immunoprecipitation.ResultsPERP expression was markedly reduced in breast cancer cells and tumor tissues compared with that in normal controls, and low PERP levels were associated with poor prognosis. PERP overexpression suppressed metastasis. Mechanistically, PERP upregulated ATF3 expression, and ATF3 bound to the HSPA6 promoter to activate its transcription. Knockdown of ATF3 or HSPA6 eliminated the antimetastatic effects of PERP.ConclusionsPERP suppresses breast cancer metastasis by inducing ATF3, which in turn activates HSPA6 transcription. This PERP-ATF3-HSPA6 axis represents a key regulatory pathway and serves as a potential therapeutic target in metastatic breast cancer.