Date of Completion

9-7-2016

Embargo Period

9-1-2016

Major Advisor

Suzy V. Torti

Associate Advisor

Christopher D. Heinen

Associate Advisor

Kevin P. Claffey

Associate Advisor

Pramod K. Srivastava

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Iron is an essential growth factor and cofactor for multiple molecular functions in the human body. It is a reactive metal and in excess is capable of participating in Fenton reactions, generating reactive oxygen species and damaging cells. Patients with the iron overload disease hemochromatosis, are at increased risk of hepatic and other cancers. Due to the necessity and toxicity of iron, it is tightly regulated. Cancerous cells have an increased demand for iron and to meet these needs, regulation of iron import (upregulation of transferrin receptor) and export (downregulation of ferroportin) proteins is altered. Differential expression of these iron genes is associated with prognosis. This has led to further analysis of the association of “iron” genes with breast cancer prognosis. The association of duodenal cytochrome b (DCYTB) in breast cancer was identified as part of a 16 gene iron regulatory gene signature (IRGS). DCYTB is a ferrireductase in duodenal enterocyte responsible for reducing dietary iron for cellular uptake. To further characterize the prognostic capability of DCYTB, we evaluated breast cancer patient microarray data in two combined cohorts totaling over 1600 patients. We found that high DCYTB expression was associated with increased probability of relapse-free survival (both local and distant). Results of array data and breast cancer tissue staining agree that DCYTB expression is reduced with increased tumor grade. We also show that patient with high DCYTB expression are more likely to benefit from Tamoxifen therapy. This association is quite interesting because previous research has shown that increased iron is associated with poor outcome in cancer. Here, however, we see an iron import protein that is associated with good prognosis. Therefore, we evaluated iron metabolism as a result of DCYTB knockdown and overexpression. Iron responsive protein expression and labile iron were not altered, suggesting that in breast cancer cell lines DCYTB functions independently of iron. Metabolism of copper and ascorbate, two known substrates of DCYTB, was also evaluated. The results of these experiments were inconclusive, but revealed potential perturbations to reactive oxygen species signaling and regulation of cytochrome p450, which will be the focus of future experiments.

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