Merlin deficiency alters the redox management program in breast cancer.
Mateus MotaBrandon J MetgeDominique C HinshawHeba A AlsheikhDongquan ChenRajeev S SamantLalita A ShevdePublished in: Molecular oncology (2021)
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.
Keyphrases
- nuclear factor
- signaling pathway
- lps induced
- oxidative stress
- pi k akt
- toll like receptor
- induced apoptosis
- poor prognosis
- metastatic breast cancer
- inflammatory response
- binding protein
- gene expression
- dna methylation
- long non coding rna
- quality improvement
- extracellular matrix
- endoplasmic reticulum stress
- childhood cancer