Abstract
Protein ubiquitination and degradation represent druggable vulnerabilities of cancer cells. We used gene expression and functional annotation analyses to identify genes in the ubiquitin pathway which are differentially expressed between normal breast and basal-like tumors. With this approach we identified 16 ubiquitin related genes overexpressed in basal-like breast cancers compared with normal breast. We then explored the association between these genes and outcomes using the KMPlotter online tool. Two genes, the ubiquitin-conjugating enzyme E2T (UBE2T) and the denticleless protein homolog (DTL) were overexpressed and linked with detrimental outcome in basal-like and luminal breast cancer patients. Furthermore, we found that UBE2T and DTL were amplified in around 12% of breast tumors based on data contained at cBioportal. In non-small cell lung adenocarcinomas, UBE2T and DTL were also amplified in around 7% of cases and linked with disease recurrence after surgical resection. No significant molecular alterations or a clear trend for clinical outcome was observed for these genes in ovarian serous cystadenocarcinoma, esophagus-stomach cancer or non-small squamous cell carcinoma. Our data suggest that UBE2T and DTL may have a role in the pathophysiology of breast and lung tumors, opening avenues for future clinical evaluation of agents targeting those proteins or their pathways.
Highlights
The identification of oncogenic vulnerabilities based on druggable genomic modifications has permitted the development of therapeutic agents[1,2]
In the present article we describe two genes involved in the ubiquitin pathway that are amplified in breast tumors and non-small cell lung adenocarcinomas, and are associated with detrimental outcome
The protein product of the Ubiquitin-conjugating enzyme E2T gene catalyzes the covalent attachment of ubiquitin to protein substrates. It is involved in the DNA repair pathway by catalyzing the monoubiquitination of the Fanconi Anemia Complex[14] and BRCA1, promoting their degradation[15]
Summary
The identification of oncogenic vulnerabilities based on druggable genomic modifications has permitted the development of therapeutic agents[1,2]. Examples include agents such as trastuzumab or lapatinib that target HER2, or B-Raf inhibitors like vemurafenib in melanoma for patients with mutations in that gene[1,2]. Targeting enzymes involved in this process is challenging as different ubiquitin proteins have been described and they participate in a wide range of different cellular functions[6,8], including regulation of cell cycle and DNA repair, in which by increasing the degradation of proteins involved in these pathways, they can facilitate tumor progression and metastasis[7,9,10,11]. When studied in other solid tumors we www.nature.com/scientificreports/
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