Merlin deficiency alters the redox management program in breast cancer

Abstract

The expression of Merlin tumor suppressor protein encoded by 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 NF2silenced cells supported reduced activity of the Nrf2 antioxidant transcription factor, concomitant with elevated expression of NADPH oxidase enzymes. Importantly, mammary specific Nf2-/in an MMTV 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.

Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2‐Notch1 upregulation and Nf2 downregulation

“…We conducted immunofluorescence analyses on mouse blastocysts that were microinjected with control shRNA or empty cDNA plasmids to examine the relationship between oxidative stress levels and the expression of Nf2/Merlin. Our findings revealed a positive correlation between increased oxidative stress and HBO treatment, along with a negative correlation with Nf2/Merlin expression, consistent with previous studies 18,21,30,32–34 . Specifically, we observed significantly decreased Nf2 immunofluorescence intensity and a substantial increase in CellROX Green staining signals in the blastocysts exposed to daily HBO treatment in vivo (Figure 2A and data not shown).…”

“…22,23,[28][29][30][31] On the other hand, studies involving cultured breast cancer and Schwann cells in vitro, as well as knockout mouse models in vivo, have revealed that the deficiency of Nf2/Merlin resulted in a notable increase in the expression of prooxidant genes and levels of ROS, while simultaneously leading to a decrease in the expression of antioxidant genes. [32][33][34] These results indicate a positive correlation between oxidative stress and the Hippo-Nf2 signaling.…”

“…Our findings revealed a positive correlation between increased oxidative stress and HBO treatment, along with a negative correlation with Nf2/Merlin expression, consistent with previous studies. 18,21,30,[32][33][34] Specifically, we observed significantly decreased Nf2 immunofluorescence intensity and a substantial increase in CellROX Green staining signals in the blastocysts exposed to daily HBO treatment in vivo (Figure 2A and data not shown). The quantification of relative immunofluorescence intensity showed a significant average decrease of 67-72% in Nf2 protein levels in the blastocysts exposed to HBO compared to those exposed to normoxia.…”

“…Furthermore, previous studies have indicated that oxidative stress, induced by hydrogen peroxide (H 2 O 2 ) treatment in vitro or through a mouse model of ischemia followed by reperfusion (I/R), can activate three key downstream effectors of the Hippo pathway: Nf2/Merlin, MST1, and YAP 22,23,28–31 . On the other hand, studies involving cultured breast cancer and Schwann cells in vitro, as well as knockout mouse models in vivo, have revealed that the deficiency of Nf2/Merlin resulted in a notable increase in the expression of prooxidant genes and levels of ROS, while simultaneously leading to a decrease in the expression of antioxidant genes 32–34 . These results indicate a positive correlation between oxidative stress and the Hippo‐Nf2 signaling.…”

BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency

“…In breast cancer cell and renal cell carcinoma lines, loss of BNC1 expression increases cell motility, which is associated with a poorer prognosis 61,62 . In some studies, loss of function of NF2 has been reported to programmatically influences the redox imbalance that orchestrates malignant attributes of mammary/breast cancer 63,64 . These results support our finding that low NF2 expression in Bnc1mutant mice results in a dysregulated cellular redox management system.…”