Dissertation
Unique iodine metabolic pathway activates the aryl hydrocarbon receptor pathway in the MCF-7 human breast cancer cell line
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2012
DOI:
https://doi.org/10.17918/00010128
Abstract
The protective effect of iodine on breast cancer and its importance in normal breast physiology has been well established through multiple studies. Iodine deficiency leads to breast dysplasia in animal models while iodine replacement can reverse iodine deficient induced dysplasia. Additionally, high iodine diets have been shown to inhibit cancer promotion in various animal models. Epidemiologic data demonstrating that areas with high iodine diets, such as Asia, have a low incidence of breast cancer suggests that iodine plays a role in human breast physiology. This is further supported by evidence that Iodine supplementation can relieve symptoms from certain benign breast diseases in human studies. Together, these data supports a role of iodine in maintaining healthy breast tissue and preventing early dysplastic and malignant changes. However, despite the strong evidence that iodine plays an important role in normal breast physiology, there are few studies that describe iodine's mechanism of action or target pathways within the breast. Microarray data identified Cytochrome P450 1A1 (CYP1A1) and other estrogen metabolizing enzymes as key genes altered in response to iodine/iodide treatment in an MCF7 in-vitro model. We found CYP1A1 up regulation to be specific to iodine (12) but not iodide (I-) in a dose and time dependent manner. Subsequently we identified the aryl hydrocarbon receptor (AhR), the key regulator of CYPA1A1, as a key mediator of iodine induction of CYP1A1. Finally, iodine gene expression profiling demonstrates significant, albeit more selective, overlap with dioxin, the prototypic ligand of the AhR. This thesis elucidates the first step in the iodine metabolic pathway and unites it to the AhR pathway, a well studied, albeit poorly understood pathway. Identifying the AhR as a key mediator of the iodine response not only affords a more direct approach to future studies on iodine but also provides key data that will hopefully help elucidate critical components of the AhR pathway. Identifying iodine's mechanisms of actions and understanding its role in human physiology will help us identify the consequences of whole-body iodine deficiency and enter an era where iodine is utilized in accordance with its true physiologic import.
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Details
- Title
- Unique iodine metabolic pathway activates the aryl hydrocarbon receptor pathway in the MCF-7 human breast cancer cell line
- Creators
- Frederick Rhode Stoddard
- Contributors
- Ari D. Brooks (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 195 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Drexel University
- Other Identifier
- 991021889090904721