AGTPBP1 promotes breast cancer progression via the EVPL/ERK signaling axis.

BACKGROUND

The role of ATP/GTP binding protein 1 (AGTPBP1), a cytosolic carboxypeptidase, in oncogenesis remains largely unexplored. Although we previously identified its tumor-promoting function in pancreatic cancer, its expression pattern, biological function, and underlying mechanisms in breast cancer remain elusive.

METHODS

AGTPBP1 expression and its clinical relevance in breast cancer were first assessed using public proteomic databases. Stable AGTPBP1 overexpression and knockdown models were established in the luminal A T47D and triple-negative MDA-MB-231 breast cancer cell lines to account for tumor heterogeneity. Malignant phenotypes were evaluated through a series of in vitro functional assays, including proliferation, colony formation, migration, and matrigel invasion assays. Mechanistic insights were gained by RNA-sequencing (with biological triplicates) and subsequent experimental validation, including rescue experiments.

RESULTS

AGTPBP1 was significantly upregulated in breast cancer tissues. Functional studies demonstrated that AGTPBP1 overexpression markedly enhanced cell proliferation, colony formation, migration and invasion, whereas its knockdown suppressed these malignant behaviors. Transcriptomic profiling revealed that AGTPBP1 was critically involved in cell adhesion and cell-cell junction pathways. We identified envoplakin (EVPL), a core desmosomal protein, as a key downstream effector, whose expression was negatively regulated by AGTPBP1. Mechanistically, AGTPBP1-mediated repression of EVPL led to the activation of the ERK signaling pathway, as evidenced by increased phosphorylation of ERK1/2. Rescue experiments confirmed that EVPL overexpression attenuated AGTPBP1-induced malignant phenotypes and ERK activation.

CONCLUSION

This study unveils a novel oncogenic role of AGTPBP1 in breast cancer. We delineate a previously unrecognized AGTPBP1/EVPL/ERK axis whereby AGTPBP1 drives tumor progression by simultaneously disrupting intercellular adhesion and activating pro-tumorigenic ERK signaling. Our findings propose AGTPBP1 as a potential therapeutic target for breast cancer intervention.