Strikingly, three USP4 mutants from breast cancer, namely L301R, S315C, and R559W, failed to upregulate endogenous BRCA1 protein level (Fig. 5a and Supplementary Fig. 5a), whereas most of other mutants could still efficiently promote the accumulation of BRCA1 like USP4 WT (Supplementary Fig. 5b–d). This evidence concerns the gene BRCA1 and breast carcinoma.