All ETDs from UAB

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.

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