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 signalingpathways, such as those related to apoptosis, cell cycle and DNA repair. In thisstudy, we found a pronounced cytosolic accumulation of the p53 protein in a panelof breast cancer specimens. Several mutations lead to p53 accumulation by disruptionof MDM2-mediated p53 degradation. However, gene sequencing revealed no p53 mutationin the majority of our samples. Through search for other possible p53 E3 ligasesby mRNA and protein expression analysis, downregulation of TNF receptor-associatedfactor 7 (TRAF7) expression was found in these breast tumors. We further identifiedTRAF7 as an E3 ligase for K48-linked ubiquitination of p53 in vitro. These resultssuggested 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 cancercohort. Collectively, TRAF7-mediated ubiquitination of p53 plays a critical rolein breast cancer development, and these insights may aid in the development ofnovel therapeutic strategies for breast cancer.