Date of Completion

8-31-2017

Embargo Period

8-28-2019

Keywords

Hepcidin, Spheroid, Iron, Breast Cancer

Major Advisor

Suzy Torti

Associate Advisor

Kevin Claffey

Associate Advisor

Christopher Heinen

Associate Advisor

Ann Cowan

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Iron is an essential nutrient for normal cellular functioning, but excess iron retention is a hallmark of breast cancer, used to fuel cancer cells proliferative demands. Breast cancer cells alter genes that control iron metabolism to promote accumulation of cellular iron. One way breast cancer cells retain iron is through decreased iron export. Breast cancer cells have reduced expression of the iron efflux pump, ferroportin (FPN). FPN is reduced by the iron regulating peptide hepcidin, which binds to FPN and triggers its degradation, resulting in decreased iron export. Hepcidin is elevated in breast cancer to promote accumulation of cellular iron. However, the pathways responsible for elevated hepcidin in breast cancer cells have never been investigated. In this thesis we utilize several culture methods to examine the full spectrum of hepcidin regulation in breast cancer including two- and three-dimensional culture of established cell lines and primary breast cells, as well as co-culture systems with stromal cells. Ultimately, we reveal a complex hepcidin regulatory network involving protein molecules and spatial cues, consisting of changes at the cellular, dimensional and microenvironmental levels. Specifically, we found regulation of hepcidin by ligands including bone morphogenetic proteins (BMPs), interleukin-6 (IL-6) and growth-differentiation factor-15 (GDF-15) in an autocrine and paracrine fashion, as well as novel regulation by the microenvironment, specifically by contribution of tumor associated fibroblasts and extracellular matrix proteins. Additionally, we reveal global changes in iron metabolism in breast cancer spheroids and that targeting enhanced iron levels present in spheroids results in disaggregation and spheroid cell death. Thus, targeting iron in breast tumors may be an attractive molecular strategy for selective killing of breast cancer cells.

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