Merlin deficiency alters the redox management program in breast cancer

Academic Article

Abstract

  • The expression of Merlin tumor suppressor protein encoded by Neurofibromin 2 (NF2) gene is remarkably decreased in metastatic breast cancer tissues. In order to recapitulate clinical evidence, we generated a unique, conditional Nf2-knockout (Nf2−/−) mouse mammary tumor model. Merlin-deficient breast tumor cells and Nf2−/− mouse embryonic fibroblasts (MEFs) displayed a robustly invasive phenotype. Moreover, Nf2−/− MEFs presented with notable alterations in redox management networks, implicating a role for Merlin in redox homeostasis. This programmatic alteration resonated with pathways that emerged from breast tumor cells engineered for Merlin deficiency. Further investigations revealed that NF2-silenced cells supported reduced activity of the Nuclear factor, erythroid 2 like 2 antioxidant transcription factor, concomitant with elevated expression of NADPH oxidase enzymes. Importantly, mammary-specific Nf2−/− in an Mouse mammary tumor virus Neu + murine breast cancer model demonstrated accelerated mammary carcinogenesis in vivo. Tumor-derived primary organoids and cell lines were characteristically invasive with evidence of a dysregulated cellular redox management system. As such, Merlin deficiency programmatically influences redox imbalance that orchestrates malignant attributes of mammary/breast cancer.
  • Published In

  • Molecular Oncology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Mota M; Metge BJ; Hinshaw DC; Alsheikh HA; Chen D; Samant RS; Shevde LA
  • Start Page

  • 942
  • End Page

  • 956
  • Volume

  • 15
  • Issue

  • 4