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 regulator 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 mutation in the majority of our samples. Through search for other possible p53 E3 ligases by mRNA and protein expression analysis, down regulation of TNF receptor-associated factor 7 (TRAF7) expression was found in these breast tumors. We further identified TRAF7 as an E3 ligase for K4-8-linked ubiquitination of p53 in vitro. These results suggested that the p53 accumulation was due to the defects of TRAF7-mediated ubiquitination. The down regulation 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.