Inverse association between MDM2 and HUWE1 protein expression levelsin human breast cancer and liposarcoma

摘要

The ubiquitin E3 ligase MDM2 is best known for its ability to suppress the tumor suppressor p53. However, MDM2 also targets other proteins for proteasomal degradation and accumulating evidence strongly suggests p53-independent roles of MDM2 in cancer. We previously reported that MDM2 promotes degradation of another ubiquitin E3 ligase HUWE1 by ubiquitination, particularly, which confers HER2⁺ breast cancer cells resistance to the HER2 inhibitor lapatinib. However, it remains unclear whether such a mechanism can operate in other cell types, independently of HER2 inhibitors. Moreover, in vivo evidence that supports HUWE1 degradation by MDM2 is missing. In the current study, we performed immunohistochemistry (IHC) to analyze expression levels of MDM2 and HUWE1 in normal organs, two breast cancer cohorts (A, n = 137 and B, n = 27), and a liposarcoma cohort (n = 45). Our results show that HUWE1 is ubiquitously expressed in healthy organs, where the oncoprotein MDM2 is undetectable. Likewise, in the majority of breast cancers regardless of their subtypes, MDM2 is below detectable levels, while HUWE1 is highly expressed. In contrast, in a subset of liposarcoma that is characterized by MDM2overexpression, only 40% of these showed detectable HUWE1 protein.Importantly, despite the inverse association between MDM2 and HUWE1 proteinlevels, gene expression analysis in independent datasets revealed no suchcorrelation at the mRNA level. Our results demonstrate the first invivo evidence to support the hypothesis of MDM2-mediated HUWE1degradation, which may help to understand the regulation of HUWE1 as well asp53-independent roles of MDM2.