Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer

p53 is a key tumor suppressor and a master regu- lator of various signaling pathways, such as those related to apoptosis, cell cycle and DNA repair. In this study, we found a pronounced cytosolic accumulation of the p53 protein in a panel of breast cancer specimens. Several mutations lead to p53 accumulation by disruption of MDM2-mediated p53 degradation. However, gene sequencing revealed no p53 muta- tion in the majority of our samples. Through search for other possible p53 E3 ligases by mRNA and protein expression analysis, downregulation of TNF receptor-associated factor 7 (TRAF7) expression was found in these breast tumors. We further identified TRAF7 as an E3 ligase for K48-linked ubiquitination of p53 in vitro. These results suggested that the p53 accumulation was due to the defects of TRAF7-mediated ubiquitination. The downregulation of TRAF7 also correlated with poor prognosis in a breast cancer cohort. Collectively, TRAF7-mediated ubiquitination of p53 plays a critical role in breast cancer development, and these insights may aid in the development of novel therapeutic strategies for breast cancer.