Manganese Superoxide Dismutase (MnSOD): A Driver of Metabolism Critical for Breast Cancer Progression

Manganese superoxide dismutase (MnSOD) is a critical mitochondrial resident enzyme responsible for the conversion of the mild oxidant superoxide anion (O2-•) to hydrogen peroxide (H2O2), a highly potent and freely diffusible reactive oxygen species (ROS). The current study identifies MnSOD overexpression as both necessary and sufficient to promote glycolytic metabolism requisite for malignant transformation and tumor progression in breast cancer. This novel pro-tumorigenic role of MnSOD is dependent on its product, mtH2O2, which acts as a primary signaling molecule resulting in the activation of AMP-activated kinase (AMPK) to initiate the glycolytic shift. We further show that MnSOD overexpression in breast cancer is due to enhanced Nrf-2 transcriptional activity as a consequence of the loss of Caveolin-1 (Cav-1), and describe novel biomarkers which may be critical in patient risk stratification as well as the assessment of therapies targeted towards highly glycolytic tumors.