Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer.

Abstract

Simple SummaryBreast cancer is a major cause of death worldwide and remains incurable in advanced stages. The dysregulation of the post-translational machinery has been found to underlie tumorigenesis and drug resistance in preclinical models but has only recently led to early trials in cancer patients. We performed an in silico analysis of the most common genomic alterations occurring in ubiquitination and ubiquitin-like SUMOylation and neddylation using data from publicly available repositories and with the aim of identifying those with prognostic and predictive value and those exploitable for therapeutic intervention. Clinical and statistical criteria were used to sort out the best candidates and the results were validated in independent datasets. UBE2T, UBE2C, and BIRC5 amplifications predicted a worse survival and poor response to therapy across different intrinsic subtypes of breast cancer. Mutated USP9X and USP7 also conferred detrimental outcome. Leveraging these molecular vulnerabilities as biomarkers or drug targets could benefit breast cancer patients.The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.