Abstract
The ubiquitin-proteasome system influences cancer progression through multiple mechanisms. Due to the extensive proteasomal modifications observed in cancer tissues, ubiquitination is closely related to various biological functions with cancer. However, the roles of ubiquitin-related genes (UbRGs) in breast cancer (BC) have not been thoroughly investigated. In this study, we retrieved 763 reliable UbRGs and identified a potential prognostic signature for breast cancer patients. Additionally, we analyzed eight overall survival-associated UbRGs using univariate Cox proportional hazard regression in the Cancer Genome Atlas (TCGA) database. Subsequently, we used Lasso-Cox risk regression analysis to generate prognostic characteristics of UbRGs associated with overall survival (OS), validated in an external cohort (GSE158309). Next, we compared differences in tumor microenvironment and drug sensitivity between subgroups, describing the potential impact of UbRGs on the landscape of the tumor immune microenvironment and their predictive significance for therapeutic resistance to different strategies. Furthermore, a nomogram model containing eight genes, histology, subtype, T status, N status, and the American Joint Committee on Cancer (AJCC) stage was constructed. Finally, in vitro and in vivo experiments validated the effects of FBXL6 and PDZRN3 on breast cancer development. In conclusion, we demonstrate that ubiquitin-related genes are closely associated with breast cancer prognosis, immune environment, and drug sensitivity. Our results offer a new insight into breast cancer treatment.