This study reveals a non-canonical function of the E3 ubiquitin ligase FBXO3 in PI3K-induced breast cancer metastasis, showing that FBXO3 binds to and protects USP4 from aspartyl aminopeptidase (DNPEP)-mediated degradation, resulting in Twist1 protein stabilization and increased tumor metastasis. This evidence concerns the gene USP4 and breast carcinoma.