A novel metadherin Delta 7 splice variant enhances triple negative breast cancer aggressiveness by modulating mitochondrial function via NF x138;B-SIRT3 axis

Metadherin (MTDH) expression inversely correlates with prognosis of several cancers including mammary carcinomas. In this work, we identified a novel splice variant of MTDH with exon7 skipping (MTDH Delta 7) and its levels were found significantly high in triple negative breast cancer (TNBC) cells and in patients diagnosed with TNBC. Selective overexpression of MTDH Delta 7 in MDA-MB-231 and BT-549 cells enhanced proliferation, invasion, and epithelial-to-mesenchymal (EMT) transition markers in comparison to its wildtype counterpart. In contrast, knockdown of MTDH Delta 7 induced antiproliferative/antiinvasive effects. Mechanistically, MTDH-NF & x138;B-p65 complex activated SIRT3 transcription by binding to its promoter that in turn enhanced MnSOD levels and promoted EMT in TNBC cells. Intriguingly, mitochondrial OCR through Complex-I and -IV, and glycolytic rate (ECAR) were significantly high in MDA-MB-231 cells stably expressing MTDH Delta 7. While depletion of SIRT3 inhibited MTDH-Wt/Delta 7-induced OCR and ECAR, knockdown of MnSOD inhibited only ECAR. In addition, MTDH-Wt/Delta 7-mediated pro-proliferative/-invasive effects were greatly obviated with either siSIRT3 or siMnSOD in these cells. The functional relevance of MTDH Delta 7 was further proved under in vivo conditions in an orthotopic mouse model of breast cancer. Mice bearing labeled MDA-MB-231 cells stably expressing MTDH Delta 7 showed significantly more tumor growth and metastatic ability to various organs in comparison to MTDH-Wt bearing mice. Taken together, MTDH Delta 7 promotes TNBC aggressiveness through enhanced mitochondrial biogenesis/function, which perhaps serves as a biomarker.