Unveiling GSPT1 as a crucial prognostic biomarker and therapeutic vulnerability in breast cancer

Abstract

Abstract Breast cancer (BRCA) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of novel biomarkers and therapeutic targets to overcome challenges such as treatment resistance and metastasis. In this study, we systematically characterized the multi-omic landscape of G1 to S phase transition protein 1 (GSPT1) in BRCA. Integrative bioinformatic analysis of public datasets revealed that GSPT1 mRNA and protein levels are significantly upregulated in BRCA across all clinical stages and molecular subtypes. To validate these findings, we performed immunohistochemical (IHC) staining on representative patient-derived tissue samples, which, complemented by transcriptomic analysis of diverse cell lines, confirmed this upregulation. High GSPT1 expression and its prevalent genomic alterations identified in public cohorts—particularly gene amplification observed in approximately 14% of cases—were strongly correlated with poor clinical outcomes, including diminished overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival (DMFS). Functional enrichment analyses indicated that GSPT1 expression is strongly associated with pathways critical for tumorigenesis, such as the cell cycle, DNA replication, and mitotic spindle organization. Furthermore, dependency analysis via the DepMap database and our experimental validation demonstrated that BRCA cells are highly dependent on GSPT1 for survival. Collectively, our findings further substantiate GSPT1 as a robust prognostic biomarker and provide translational evidence supporting its feasibility as a molecular glue-targetable vulnerability for precision oncology in BRCA.