USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration

Breast cancer (BC), the most frequent tumor entity in women globally, shows a high therapeutic response in early and non-metastatic stages. However, triple-negative BC (TNBC), enriched with cancer stem cells (CSCs), presents significant challenges due to its chemoresistant and metastatic nature. Ubiquitin Specific Proteinase 22 (USP22) has emerged as a key player in promoting CSC functions, contributing to resistance to conventional therapies, tumor relapse, metastasis, and poor survival across various cancers, including BC. The specific role of USP22 in TNBC, however, remains underexplored. In this study, we employed the MMTV-cre, Usp22fl/fl transgenic mouse model to investigate USP22's influence on stem cell-like properties in mammary tissue. High-throughput transcriptomic analyses, combined with publicly available patient data and TNBC culture models, were utilized to elucidate USP22's role in CSC characteristics of TNBC. Our findings reveal that USP22 enhances CSC properties and drug tolerance by supporting oxidative phosphorylation, a key factor in the poor response to conventional therapies in aggressive BC subtypes. The study uncovers a novel tumor-supportive role of USP22 in sustaining cellular respiration, which contributes to the drug-tolerant behavior of HER2+-BC and TNBC cells. This highlights USP22 as a potential therapeutic target, offering new avenues to optimize standard treatments and address the aggressiveness of these malignancies.