Date of Award

8-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Hwa-Chain Robert Wang

Committee Members

Stephen Kania, Agricola Odoi, Jonathan wall

Abstract

Chronic exposure to environmental carcinogens may trigger development of sporadic breast cancer, a multistep tumorigenesis process involving aggregation of genetic and epigenetic alterations, resulting in a serial progression from a non-cancerous to precancerous stage and eventually malignant breast cancer. In this study, I used a cellular model that simulates induction and progression of chronic breast cell carcinogenesis using concentrations of environmental carcinogens which are achievable in blood or plasma. Process of carcinogenesis was measured by certain detectable constitutive and transient end points including acquisition of cancer-associated properties, increased ROS prodiction, cell proliferation, DNA damage and activation of Erk-Nox pathway which could be targeted by non-cytotoxic dosages of dietary compounds. Triclocarban (TCC) is an antimicrobial agent present in personal care products. This study was designed to investigate the ability of TCC to act as a co-carcinogen and therefore induce premalignant breast cell carcinogenesis and enhance 2-Amino-1-methyl- 6-phenylimidazo(4,5-b)pyridine (PhIP)-induced breast cell carcinogenesis in MCF10A cells. My results showed that repeated treatments with TCC induced cancer-associated properties of reduced dependence on growth factors and anchorage-independent growth in MCF10A cells. Concurrently, there was increased ROS production, cell proliferation and upregulation of Erk-Nox pathway in response to single as well as long term exposure to TCC. Curcumin, a polyphenolic component extracted from the rhizome, Curcuma longa, was able to suppress these transient and constitutive endpoints induced in breast cells exposed to TCC. MCF10A cells were also subjected to either individual or combined TCC and PhIP exposure. Cells co-treated with TCC and PhIP had significantly higher levels of cancer-associated properties, ROS production, cell proliferation and Erk- Nox pathway activation as compared to cells treated with PhIP alone. The transient and constitutive endpoints induced by co-treatement with TCC and PhIP were significantly suppressed by mimosine, a non protein amino acid isolated from Mimosa pudica and Ergosterol, a sterol found in cell membranes of fungi. These results proved that TCC has the ability to induce breast cell premalignancy and enhance breast cell carcinogenesis induced by PhIP in MCF10A cells. Furthermore, curcumin, ergosterol and mimosine could play promising roles in prevention of sporadic breast cancer.

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