E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications

Abstract

Female breast cancer has become the most commonly occurring cancer worldwide. Although it has a good prognosis under early diagnosis and appropriate treatment, breast cancer metastasis drastically causes mortality. The process of metastasis, which includes cell epithelial–mesenchymal transition, invasion, migration, and colonization, is a multistep cascade of molecular events directed by gene mutations and altered protein expressions. Ubiquitin modification of proteins plays a common role in most of the biological processes. E3 ubiquitin ligase, the key regulator of protein ubiquitination, determines the fate of ubiquitinated proteins. E3 ubiquitin ligases target a broad spectrum of substrates. The aberrant functions of many E3 ubiquitin ligases can affect the biological behavior of cancer cells, including breast cancer metastasis. In this review, we provide an overview of these ligases, summarize the metastatic processes in which E3s are involved, and comprehensively describe the roles of E3 ubiquitin ligases. Furthermore, we classified E3 ubiquitin ligases based on their structure and analyzed them with the survival of breast cancer patients. Finally, we consider how our knowledge can be used for E3s’ potency in the therapeutic intervention or prognostic assessment of metastatic breast cancer.

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer

“…Although median levels of bTMB and bCNB were not significantly increased at the time of clinical progression relative to baseline, we observed enrichment of individual alterations previously implicated in endocrine and/or CDK4/6i treatment resistance including AR, AURKA, CCND1, CDKN2A, ESR1, FGFR1, MYC and RB1 (47). We also observed enrichment of alterations in genes less commonly associated with ET and CDK4/6i treatment resistance, which encode a variety of oncogenic proteins, including CBL, a member of the RING finger ubiquitin ligase family that regulates receptor tyrosine kinase signaling (56)(57)(58); KMT2D, a methyltransferase involved in estrogen receptor recruitment and activation (59); MUC12, a glycosylated transmembrane protein in the mucin family implicated in the regulation of proliferation, invasion and metastatic potential (60)(61)(62); and PREX2, a guanine nucleotide exchange factor that regulates cancer cell motility and invasion (63,64). Many of these novel alterations are not covered by targeted sequencing panels, underscoring the value of the extended WES to identify diverse mechanisms of resistance.…”

Robust Identification of Differential Gene Expression Patterns from Multiple Transcriptomics Datasets for Early Diagnosis, Prognosis, and Therapies for Breast Cancer

“…Different types of post-translational modifications (PTMs) of proteins are associated with different types of cancer. Some studies reported that the phosphorylation, succinylation, and ubiquitination sites of proteins are the BC-causing PTM sites [110,[112][113][114]. Therefore, we verified the resistance power of the top-ranked three ligands (Suramin, Rifaximin, and Telmisartan) against the phosphorylation, succinylation, and ubiquitination sites of BC-causing HubGs-mediated receptor proteins by molecular docking analysis.…”

The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma

“…RING finger (RNF) proteins comprise a large family of proteins which play pivotal roles in protein ubiquitination. Ubiquitination is mainly involved in mediating protein degradation, which in turn regulates cellular activities [ 8 , 9 ]. It has been reported that ubiquitination participates in lots of intracellular biological processes, such as affecting DNA damage repair, modulating cell metabolism, regulating cell death, and altering therapeutic effect [ 10 ].…”