In conclusion, RNF5 suppresses EphA2 by inducing its ubiquitination and degradation; thus, RNF5 inhibition by genetic approaches or inhibitors increases EphA2 level and promotes its tumor-suppressive function by decreasing EphA2 S897 phosphorylation and increasing EphA2 Y772 phosphorylation, decreasing ERK activation and increasing p53 expression, and consequently suppressing tumorigenesis of ER-positive HER2-negative breast cancers. Here, ESR1 is linked to breast cancer.