Together, our data support a context-dependent role of RNF40 and H2B monoubiquitination in breast carcinogenesis and suggest that the RNF20/RNF40 E3 ubiquitin ligase and/or its upstream regulators or downstream targets may serve as attractive targets for the development of new anticancer strategies in HER2+-BC (Fig. 6). Here, H2BC21 is linked to breast cancer.