Targeting the MAGED2-TRIM28-FLNC axis overcomes chemoresistance in TNBC via EMT suppression

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor response to chemotherapy. Fewer than 40% of patients achieve a complete pathological response to neoadjuvant chemotherapy, demonstrating the chemoresistance characteristic of TNBC. Here, we analyze proteomic and transcriptomic datasets of TNBC patients treated with neoadjuvant chemotherapy and identify MAGED2 as a critical regulator of chemoresistance. Elevated MAGED2 expression in TNBC cells is associated with poor treatment response. Both in vitro and in vivo experiments demonstrate that MAGED2 promotes epirubicin resistance in TNBC. Mechanistically, MAGED2 interacts with TRIM28 to form an E3 ubiquitin ligase complex. MAGED2 enhances the ubiquitin ligase activity of TRIM28. MAGED2 L278/L279 residues are essential for its interaction with TRIM28. The interaction promotes MAGED2-induced epirubicin resistance. Further biochemical assays identify FLNC as a new target protein of the MAGED2-TRIM28 complex, which functions as a downstream effector of MAGED2-induced chemoresistance. The MAGED2-TRIM28 complex interacts with FLNC, resulting in its ubiquitination and subsequent proteasomal degradation. Loss of FLNC activates EMT, a well-established driver of chemoresistance. Notably, targeting TRIM28 via AAV-mediated gene therapy reverses MAGED2-induced epirubicin resistance in vivo, offering a promising therapeutic approach to overcome chemoresistance in TNBC.