biostudies-literatureGeng SYong MengMing-qing Gao1318https://www.ebi.ac.uk/biostudies/studies/S-EPMC12466986biostudies-literatureUnknown15(9)Breast cancer (BC) remains a leading cause of cancer-related mortality among women globally, and the role of cancer-associated fibroblasts (CAFs) in promoting BC progression is well established. Ixazomib, a proteasome inhibitor approved for the treatment of multiple myeloma, has demonstrated therapeutic potential in BC in preclinical trials. However, whether its efficacy is influenced by the tumor microenvironment, particularly CAFs, remains unclear. This study aims to investigate the role of CAFs with high expression of Activin A (encoded by INHBA) in modulating the sensitivity of BC cells to ixazomib. We demonstrate that ixazomib exhibited significant cytotoxicity in BC cells, but high-INHBA CAFs compromise ixazomib cytotoxicity through ERK-mediated proteasome suppression, reversible by BiomoleculesActivin A Secreted by Cancer-Associated Fibroblasts Reduces the Sensitivity of Breast Cancer Cells to Ixazomib via Inhibition of Proteasome Activity.PMC12466986No.363042005143No. Y2023ms0001Geng SLiu HGao MWang SGao JLiu SMeng YNiu YfalseActivin A Secreted by Cancer-Associated Fibroblasts Reduces the Sensitivity of Breast Cancer Cells to Ixazomib via Inhibition of Proteasome Activity.Breast cancer (BC) remains a leading cause of cancer-related mortality among women globally, and the role of cancer-associated fibroblasts (CAFs) in promoting BC progression is well established. Ixazomib, a proteasome inhibitor approved for the treatment of multiple myeloma, has demonstrated therapeutic potential in BC in preclinical trials. However, whether its efficacy is influenced by the tumor microenvironment, particularly CAFs, remains unclear. This study aims to investigate the role of CAFs with high expression of Activin A (encoded by INHBA) in modulating the sensitivity of BC cells to ixazomib. We demonstrate that ixazomib exhibited significant cytotoxicity in BC cells, but high-INHBA CAFs compromise ixazomib cytotoxicity through ERK-mediated proteasome suppression, reversible by 2025-01-01T00:00:00Z2025 Sep2026-05-02T03:17:48.655Z2026-05-02T03:09:49.655ZS-EPMC124669864100862510.3390/biom15091318