Graduation Date

5-2013

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Kiowa Bower, Ph.D.

First Reader

Maggie Louie, Ph.D.

Second Reader

Mary Sevigny, Ph.D.

Abstract

Cadmium is an environmental contaminant that enters the body usually through diet or cigarette smoke. Exposure to cadmium has been associated with the development of breast cancer. Recent studies have suggested that cadmium functions as an endocrine disruptor and mimics the actions of estrogen in breast cancer cells by activating the receptor (ER) to promote breast cancer cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure has been unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand and elucidate the effects of prolonged, low-level cadmium exposure and its role in breast cancer progression. Therefore, this study aims to investigate the chronic effects of cadmium exposure on breast cancer progression. An MCF7 breast cancer cell line (MCF7-Cd) chronically exposed to 10-7M CdCl2 was developed and serves as a model system to facilitate studies on the effects of chronic cadmium exposure on breast cancer progression. The data presented here suggest that prolonged cadmium exposure results in the development of more aggressive cancer phenotypes increased cell growth, migration, and invasion. Cells exposed to cadmium were shown to express higher levels of SDF-1— a chemokine known to contribute to cancer cell growth, migration and invasion. Results from this study demonstrated

vithat the expression of SDF-1 was not only dependent on ER but also on c-jun and c-fos, and the interactions between ER with c-jun and c-fos were significantly increased at both the protein and transcription levels in cells chronically exposed to cadmium. Additionally, the data showed that chronic cadmium exposure was able to disrupt cell-cell adhesion by down-regulating Ecadherin expression, which led to relocation of active -catenin to the nucleus, and in turn led to increased metastasis and invasion. The work presented here provides a mechanistic link between chronic cadmium exposure, ER, and breast carcinogenesis and demonstrates that prolonged cadmium exposure, even at low levels, contributes to the progression of breast cancer.

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