eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development

Abstract

Abstract.It is now widely recognized that translation factors are involved in cancer development and that components of the translation machinery that are deregulated in cancer cells may become targets for cancer therapy. The eukaryotic Release Factor 3 (eRF3) is a GTPase that associates with eRF1 in a complex that mediates translation termination. eRF3a/ GSPT1 first exon contains a (GGC)n expansion coding for proteins with different N-terminal extremities. Herein we show that the longer allele (12-GGC) is present in 5.1% (7/137) of the breast cancer patients analysed and is absent in the control population (0/135), corresponding to an increased risk for cancer development, as revealed by Odds Ratio analysis. mRNA quantification suggests that patients with the 12-GGC allele overexpress eRF3a/GSPT1 in tumor tissues relative to the normal adjacent tissues. However, using an in vivo assay for translation termination in HEK293 cells, we do not detect any difference in the activity of the eRF3a proteins encoded by the various eRF3a/GSPT1 alleles. Although the connection between the presence of eRF3a/GSPT1 12-GGC allele and tumorigenesis is still unknown, our data suggest that the presence of the 12-GGC allele provides a potential novel risk marker for various types of cancer.

Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators

“…Indeed, GSPT1 has been found to be overexpressed and oncogenic in a number of cancers, 43 including gastric, 44 colorectal, 45 lung, 46 and breast cancers. 47 To investigate GSPT1 expression in pediatric cancer, we turned to St. Jude’s PeCAN Portal, 48 a web application, which provides RNA sequencing (RNA-seq) data for 928 pediatric tumors. 49 This analysis showed that GSPT1 is overexpressed in many pediatric cancers, but mostly in hematopoietic malignancies (71%) including B-ALL, T-ALL, and AML (Supp.…”

In silico analysis of differentially expressed-aberrantly methylated genes in breast cancer for prognostic and therapeutic targets

“…Besides, the role in terminating protein translation, this multifunctional GTPase is highly involved in mitosis and apoptosis [16]. GSPT1gene, plays an important role in biological process and is highly upregulated in BC [17]. It has been shown that GSTP1 interact with GAPDH to activate its activity and inactivation of GSTP1 damages glycolytic metabolism after the GAPDH step to impair ATP generation, fatty acid and nucleotide metabolism, and oncogenic signalling pathways [18].…”

Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

“…In 2018, Wang et al 32 analyzed gene expression in total RNA extracted from breast cancer samples and identified five genes that could be used as potential prognostic biomarkers or therapeutic targets for triple‐negative breast cancer, including GSPT1. Malta‐Vacas et al 107 also showed that the longer GSPT1 allele (12‐GGC) existed in 5.1% of breast cancer patients. It has been demonstrated that the 12‐GGC allele is associated with the development of cancer by GSPT1 through the regulation of mRNA degradation or translation efficiency to the loss of protein generation function 79 .…”

“…106 In 2018, Wang et al 32 analyzed gene expression in total RNA extracted from breast cancer samples and identified five genes that could be used as potential prognostic biomarkers or therapeutic targets for triple-negative breast cancer, including GSPT1. Malta-Vacas et al 107 also showed that the longer GSPT1 allele (12-GGC) existed in 5.1% of breast cancer patients.…”