In conclusion, our results present a mechanism by which RNF208, an estrogen-inducible E3 ligase, facilitates K27-linked polyubiquitin-mediated proteasomal degradation of soluble Vimentin by targeting phosphorylated Vimentin at Ser39, thereby exerting a unique function of RNF208 in breast cancer progression. The gene discussed is RNF208; the disease is breast cancer.