Date of Award

1-1-2017

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xx, 122 pages) : illustrations (some color)

Dissertation/Thesis Chair

Douglas S Conklin

Committee Members

Martin P Tenniswood, Bruce J Herron, Fiona Ginty, Jason I Herschkowitz, Erasmus Schneider

Keywords

Breast, Cancer cells, Lipids, Charcot-Marie-Tooth disease, Glycolysis, Gene expression

Subject Categories

Biochemistry | Cell Biology | Oncology

Abstract

Altered carbohydrate and lipid metabolism are increasingly well characterized hallmarks of aggressive breast cancers. While aerobic glycolysis, or “the Warburg effect”, is a well-established metabolic adaptation exploited by tumor cells, the understanding of unique aspects of cancer lipid metabolism lags behind. This is especially true regarding the coordination of complex lipid synthesis and trafficking pathways, which remains poorly understood. N-Myc Downstream Regulated Gene1 (NDRG1) is overexpressed in many solid tumors, but its function is unclear. The importance of NDRG1 is best exemplified by the effect of null mutations on human physiology: inactivating mutations give rise to the severe autosomal recessive demyelinating peripheral neuropathy Chracot-Marie-Tooth Disease type 4D (CMT4D). The resulting defect in the lipid metabolism intensive myelination process suggests that NDRG1 functions in lipid synthesis or trafficking, but its precise role in the pathology of CMT4D remains unknown. In order to better understand its possible roles in breast cancer, clinical and genomic attributes of NDRG1 were examined. A meta-analysis of eighteen solid tumor types shows that NDRG1 expression correlates with a glycolytic and hypoxia regulated gene expression profile across solid tumor types, linking its expression with elements that contribute directly to the characteristic adaptive metabolism associated with the Warburg effect. In addition to its association with altered metabolic gene expression signatures, analysis of clinical outcomes in patients with high NDRG1 expression show that it is tightly linked with breast cancer metastasis and mortality.

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