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

Abstract

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.

Ubiquitin-conjugating enzyme 2C (UBE2C) is a poor prognostic biomarker in invasive breast cancer

“…In addition, therapeutic agents targeting UBE2C would synergise the effect of other therapies including chemotherapy, anti-oestrogen medications and radiation. Previous studies showed that overexpression of UBE2C reduces the therapeutic potency of letrozole, tamoxifen, doxorubicin and leads to radio-resistance in various BC cell lines [ 37 , 38 , 43 ]. These findings highlight the importance of further investigating the therapeutic and predictive potential of UBE2C expression in BC.…”

Diverse roles of UBE2T in cancer (Review)

“…Various genes, including UBE2T, were found to be associated with an unfavourable prognosis in each BrC subtype (54). High expression of UBE2T indicated a lower pathological complete remission rate in patients with TNBC after neoadjuvant chemotherapy, and in patients with luminal BrC with tumor recurrence within 5 years after endocrine therapy or chemotherapy (96). Compared with that in the normal breast epithelial cell line MCF-10A, the expression of UBE2T was upregulated in BrC cells.…”

Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer

“…The relationship between gene expression levels and patient clinical prognosis in terms of relapse-free survival (RFS) and overall survival (OS) was evaluated using the Kaplan-Meier Plotter platform, as described previously [28,29] (accessed on 6 June 2020). This tool used gene expression and survival data from 7830 breast tumors (sources include GEO, EGA and TCGA).…”