Here, we report that UCH-L1 can deubiquitinate and stabilize EGFR, which inhibits ERα expression by transcriptional repression, and that silencing UCH-L1 expression or inhibiting the enzyme activity can up-regulate ERα expression and enhance the sensitivity of ERα (-) breast cancer cells to tamoxifen and fulvestrant. This evidence concerns the gene ESR1 and breast carcinoma.