Abstract
Triple-negative breast cancer (TNBC) exhibits high intrinsic chemoresistance leading to poor prognosis. We identified circ(-)0008536 as a key regulator of doxorubicin (DOX) resistance through integrated transcriptomic analysis, validated by Sanger sequencing and fluorescence in situ hybridization. Circ(-)0008536 expression is significantly downregulated in DOX-resistant TNBC patient tissues and cell models, with reduced levels correlating with adverse clinical outcomes. Functionally, including CCK-8 viability assays, EdU proliferation assays, and Annexin V/PI apoptosis assays demonstrated that circ(-)0008536 overexpression resensitizes resistant cells to DOX. Mechanistically, circ(-)0008536 functions as a competitive endogenous RNA by sequestering miR-382-5p, leading to derepression of the tumor suppressor GGNBP2. This regulatory axis was rigorously evidenced by direct miR-382-5p binding to circ(-)0008536 and GGNBP2 3'UTR (dual-luciferase and RIP assays), abrogation of chemosensitivity upon miR-382-5p mimic or GGNBP2 shRNA intervention, and in vivo suppression of tumor growth with enhanced apoptosis in circ(-)0008536-overexpressing xenografts. Our findings establish circ(-)0008536 as a dual-function prognostic biomarker and therapeutic target for overcoming TNBC chemoresistance through the miR-382-5p/GGNBP2 pathway.