Merlin deficiency alters the redox management program in breast cancer

• Published in: Molecular oncology 2021-04, Vol.15 (4), p.942-956
• Main Authors: Mota, Mateus, Metge, Brandon J., Hinshaw, Dominique C., Alsheikh, Heba A., Chen, Dongquan, Samant, Rajeev S., Shevde, Lalita A.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; breast; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinogenesis; Cell Line, Tumor; DUOX; Embryo fibroblasts; ErbB-2 protein; Fibroblasts; Gene expression; Homeostasis; Invasiveness; Kinases; Laboratories; merlin; Metabolism; Metastases; Mice; Mice, Inbred BALB C; Mice, Knockout; Mutation; NAD(P)H oxidase; Neurofibromin 1; Neurofibromin 2; Neurofibromin 2 - genetics; NOX; NRF2; Organoids; Oxidation-Reduction; Oxidative Stress; Phenotypes; Phosphatase; Proteins; Reagents; ROS; Tumor cells; Tumor suppressor genes; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12896

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. Merlin‐deficient cells have an under‐functioning Nuclear factor, erythroid 2 like 2 antioxidant system, as well as a NOX‐enabled redox production system in hyperdrive. This leads to intensified oxidative stress that converges upon unrestricted cell growth and intensification of malignant attributes. Thus, Merlin deficiency disables the cellular redox management system. The findings uncover a novel mechanism by which Merlin intersects with redox homeostasis in restricting malignant characteristics.