Project description: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.
Project description:Cervical cancer treatments sometimes prove ineffective, indicating a need for personalized therapies. The present study demonstrate a strong correlation between high levels of the RNF20/RNF40 protein complex and aggressive cervical cancer. Our transcriptome analyzes uncovered a previously unknown role of this protein complex regulating peroxisomal pathway genes, which are crucial for lipid metabolism and the balance of reactive oxygen species. The loss of RNF20/RNF40 leads to reduced effectiveness of these genes, increasing lipid peroxidation and inducing a form of programmed cell death known as ferroptosis. These findings suggest that targeting the RNF20/RNF40 protein complex and its regulation capabilities could lead to new treatments for aggressive cervical cancer.