Consequently, RNF5 depletion increased cell adhesion and decreased cell migration and then inhibited the growth of xenograft tumors derived from HER2-negative breast cancer cells with increased EphA2 levels and altered EphA2 phosphorylation; these findings identified a novel interplay between RNF5 and EphA2 and a potential therapeutic approach for ER-positive, HER2-negative breast cancers. This evidence concerns the gene ESR1 and breast cancer.