Yang Y, Zhao J, Mao Y, Lin G, Li F, Jiang Z

Tamoxifen (TAM) resistance is a critical clinical challenge in the treatment of ERa+?breast cancer. However, the underlying mechanisms involved in TAM-resistance are not fully understood. Here we study the efficacy of UBR5 in predicting TAM-resistance in ERa+?breast cancer.Western blot RT-PCR and IHC staining were used to evaluate UBR5 protein and ...

Read More

mRNA levels in ERa+?breast cancer cell and tissues. MTT assays and colony formation assays were used to measure cell proliferation. The xeno-graft tumor model was used for in vivo study. We performed protein stability assay and ubiquitin assay to detect ?-catenin protein degradation. Immuno-precipitation assay was used to detect the interaction between UBR5 and ?-catenin. The ubiquitin-based immuno-precipitation based assay was used to detect the ubiquitination of ?-catenin.High UBR5 expression was correlated with poor prognosis in ER+?breast cancer. Importantly, UBR5 expression was remarkably upregulated in TAM-refractory breast cancer tissues compared with their primary paired TAM-untreated tissues. Additionally, UBR5 overexpression caused tamoxifen-resistance in vitro, whereas UBR5 knockdown increased TAM sensitivity. Mechanistic investigations revealed that UBR5 overexpression, through its ubiquitin ligase catalyzing activity, led to up-regulation of ?-catenin expression and activity. Finally, our results confirmed that TAM-resistance promoting effects by UBR5 in ERa+?breast cancer cells was at least partly due to ?-catenin stabilization, and inhibition of the UBR5/?-catenin signaling re-sensitizing the resistant breast cancer cells to tamoxifen in vivo.These findings suggested that UBR5/?-catenin signaling might be a potential therapeutic target for TAM-resistant ERa+?breast cancer.

Date: Dec. 01, 2020

View in: Pubmed Google Scholar

229964