UBASH3B promotes tamoxifen resistance and could be negatively regulated by ESR1

Abstract

Purpose: To explore the prognostic value of UBASH3B in ER+ breast cancer patients and explore potential molecular mechanisms. Materials and Methods: Datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were re-analyzed to explore the association between UBASH3B and the progression of ER+ breast cancer. Kaplan-Meier plot analysis with a total of 734 ER+ samples and Gene Set Enrichment Analysis with 632 samples were used in the study. Results: High expression of UBASH3B is negatively correlated with distant metastasis free survival (DMFS, P = 0.01, P = 0.045, P = 0.04 in 2 independent datasets and a merged dataset, respectively), disease specific survival (DSS, P = 0.028) and disease free survival (DFS, P = 0.0052, P = 0.011, P = 0.016 in 3 independent datasets, respectively) in ER+ breast cancer patients. Subset analysis found that UBASH3B also has prognostic value on both lymph node positive and negative sub-populations with ER+ breast cancer. This study also demonstrates that UBASH3B expression is tightly associated with tamoxifen resistance and TP53 mutation, which explains the association between UBASH3B and poor prognosis of ER+ breast cancer. Further analyses show that the expression of UBASH3B is affected by promoter methylation and copy number loss. Besides, UBASH3B is inversely correlated with ER and down-regulated by ER. Importantly, we find cisplatin could be a therapeutic option targeting on UBASH3B in clinical settings. Conclusions: UBASH3B is negatively regulated by ER and confers poor outcome in ER+ breast cancer patients. Cisplatin is a potential therapeutic option for the management of breast cancer patients with high expression of UBASH3B.