Modulation of Redox Environment Increases Breast Cancer Aggressiveness

Since analysis of breast cancers in The Cancer Genome Atlas database had revealed strong positive correlation between a tumor's EMT (epithelial - mesenchymal transition) score and the expression of the manganese superoxide dismutase (MnSOD) enzyme, investigators at the National University of Singapore (Singapore) sought to assess the involvement of MnSOD during the switch between epithelial-like and mesenchymal-like phenotypes in breast carcinomas.

As a member of the iron/manganese superoxide dismutase family, this enzyme transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen. This function allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and, as a result, confer protection against cell death. As a result, this protein plays an anti-apoptotic and pro-carcinogenic role against oxidative stress, ionizing radiation, and inflammatory cytokines.

The investigators reported in the August 2016 issue of the journal Antioxidants & Redox Signaling that they had observed the overexpression of MnSOD in mesenchymal-like breast cancers that exhibited increased migratory, invasive, and metastatic capacities. On the other hand, repression of MnSOD induced an epithelial phenotype with a reduction in EMT markers and cells' scattering, invasive, and motile capacity.

The positive correlation between MnSOD and EMT score was significant and consistent across all breast cancer subtypes. Similarly, a positive correlation of EMT score and MnSOD expression was observed in established cell lines derived from breast cancers exhibiting phenotypes ranging from the most epithelial to the most mesenchymal.

The investigators proposed that at the mechanistic level MnSOD appeared to drive epithelial to mesenchymal transition via its ability to modulate the cellular redox environment by adjusting the ratio of superoxide to hydrogen peroxide.

"By suppressing MnSOD expression or its activity in triple negative breast cancer patients, we are able to make the tumor cells less aggressive and more sensitive to chemotherapy," said senior author Dr. Alan Prem Kumar, principal associate in the Cancer Science Institute of Singapore at the National University of Singapore.

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