SDCBP drives tumor progression and metformin resistance by stabilizing BACH1 in triple-negative breast cancer cells

BTB domain and CNC homology 1, a heme-binding and redox-sensitive transcription factor, is highly expressed and regulates tumor progression and metastasis in triple-negative breast cancer. However, the molecular mechanisms regulating BACH1 stability and degradation in TNBC remain unclear. Here, we show that SDCBP, a tandem PDZ domain protein, stabilizes BACH1 in TNBC cells. SDCBP induces tumor progression and metastasis in TNBC cells and mouse models by stabilizing BACH1. SDCBP disassembles the SCFFBXO22-BACH1 complex through its PDZ1 domain, which prevents BACH1 proteasomal degradation. The antioxidant N-acetyl cysteine induces BACH1 expression by upregulating SDCBP, but not heme oxygenase-1. SDCBP inhibition enhances the anti-tumor efficacy of metformin in TNBC tumor-bearing mice by upregulating BACH1-regulated electron transport chain genes. These data demonstrate the functional impact of SDCBP on BACH1 stabilization, implicating the SDCBP-BACH1 axis as a potential target for preventing metastasis and enhancing ETC inhibitor efficacy in TNBC treatment.