Mangenese superoxide dismutase (MnSOD) promotes stem‐like cell phenotypes in breast cancer

Abstract

It is becoming increasingly clear that a small subpopulation of cells within tumors displaying stem cell characteristics drive tumor resistance to therapy, recurrence and metastasis. These cells are generally referred to as cancer stem cells (CSC). Reactive oxygen species (ROS) are active signaling metabolites produced in mitochondria and to a significance extent serve as determinants of cellular reprogramming to stemness. In our study we found that a primary ROS detoxifying enzyme MnSOD is dysregulated in breast cancer and that higher levels of MnSOD expression are associated with lowest survival odds in patients with tumors displaying a MnSODhigh molecular signature. In primary breast tumor cell line MCF7, overexpression of MnSOD leads to higher expression of stemness markers (Oct4, Sox2 and Nanog), increased stem cell population, and upregulation of cancer stem cell regulator hypoxia‐induced factor HIF2α transcription factor. Also, MCF7 cells which are amongst the least invasive breast cancer cell lines show significantly enhanced colony forming capacity and invasiveness ex vivo, and metastatic potential in mice. Silencing of HIF2α reversed the effect of MnSOD ectopic expression in MCF7. Altogether our results indicate that there is a MnSODhigh/HIF2α phenotype in breast cancer that displays stem‐like cell characteristics which may be involved in treatment resistance and metastatic recurrence in a subgroup of patients displaying MnSODhigh tumors.Support or Funding InformationThis research supported by the U.S. Department of Defense (ARO #61758‐LS) to M.G.B, the NCRR/NIH (S10RR027848) to M.G.B.