Advisory Committee Chair
Lalita Shevde-Samant
Advisory Committee Members
Joanne Murphy-Ullrich
Rajeev Samant
Ralph Sanderson
Sunil Sudarshan
Document Type
Dissertation
Date of Award
2020
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
The tumor suppressor Merlin is encoded by Neurofibromin 2 (NF2) gene. Merlin is predominantly located in the cell cortex where regulates cell proliferation by mediating cell contact-dependent growth inhibition. Metastatic breast cancer tissues presented with a remarkable loss of Merlin protein, revealing clinical relevance of Merlin. In order to examine the cellular effect of Merlin deficiency, breast cancer cell lines were silenced for NF2. Additionally, to assess the impact of Merlin loss at the organismal level, a mammary-specific NF2 knockout mouse mammary tumor model was engineered. Merlin deficiency induced a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Furthermore, Merlin deficiency resulted in accumulation of reactive oxygen species (ROS) as a consequence of defective redox management and increased expression of ROS-producing enzymes. These two outcomes of Merlin deficiency in breast cancer cells yield novel insight into Merlin’s functions beyond its recognized role in halting cell proliferation through abolishing mitogenic pathways. Mechanistically, the research demonstrates how Merlin deficiency compromises redox homeostasis and alters cellular bioenergetics in breast cancer. This expands the knowledge about Merlin functions as a tumor suppressor and contributes to the identification of potential therapeutic targets to overcome aberrant behaviors enhanced by Merlin deficiency.
Recommended Citation
Mota, Mateus, "Deficiency Of Tumor Suppressor Merlin Induces Metabolic Reprogramming In Breast Cancer" (2020). All ETDs from UAB. 867.
https://digitalcommons.library.uab.edu/etd-collection/867