Targeting TDP-43-activated GRP78/endoplasmic reticulum stress axis suppresses triple-negative breast cancer progression

Abstract

The TAR DNA-binding protein-43 (TDP-43), a highly conserved DNA/RNA binding protein encoded by the TARDBP gene, has garnered extensive scientific attention in the realm of neurodegenerative diseases. Notably, its association with malignant tumors has become increasingly apparent in recent years. This investigation aims to examine the role of TDP-43 in triple-negative breast cancer (TNBC) and to clarify the underlying mechanisms. Bioinformatics analysis showed that TDP-43 was substantially up-regulated in breast cancer tissues. Elevated TDP-43 expression stimulated TNBC cell proliferation and migration in vitro, and accelerated tumor progression in vivo. TDP-43 was identified as a promoter of tumor growth, with its inhibition resulting in a significant impediment to cell growth. Additionally, the overexpression of Glucose-regulated protein 78 (GRP78) counteracted the suppressive effect on cell proliferation and migration observed upon TDP-43 knockdown, affirming TDP-43′s critical role in breast cancer cell proliferation and migration. Mechanistic investigations have demonstrated that TDP-43 binds directly to GRP78 mRNA, stimulating its expression. The up-regulation of GRP78, a master regulator of the unfolded protein response, activates the inositol-requiring enzyme 1 alpha (IRE1α) pathway, exacerbating endoplasmic reticulum (ER) stress. Consequently, this process enhances the proliferation and migration of TNBC cells, contributing significantly to tumor progression. Here, we demonstrate that TDP-43 promotes cell proliferation and migration by regulating ER stress in breast cancer, offering valuable insights into the mechanistic intricacies of TDP-43 in TNBC and holding potential implications for precision treatments in this context.