Doctoral Dissertations

Date of Award

12-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Hwa-Chain R. Wang

Committee Members

Ranjan Ganguly, Brynn Voy, Hong Guo

Abstract

Most breast cancers occur sporadically due to long-term exposure to low-dose carcinogens present in our environment and diet. American lifestyles involve frequent exposures to smoke, polluted air, and high temperature-cooked meats comprising multiple carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[α[alpha]]pyrene (B[α[alpha]]P), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). To investigate whether these carcinogens may act together to enhance breast cell carcinogenesis, we used our chronically-induced breast cell carcinogenesis model wherein we repeatedly expose non-cancerous human breast epithelial MCF10A cells to physiologically-achievable doses of carcinogens to progressively induce cellular acquisition of cancer-associated properties including reduced dependence on growth factors, anchorage-independent growth, increased cell proliferation, migration and invasion and enriched stem-like cell population. These properties are then used as targets to identify dietary agents capable of blocking carcinogen-induced breast cell carcinogenesis.

In the first part of this research (Chapter 2), we demonstrated that cumulative exposures to combined NNK and B[α[alpha]]P (NB) holistically enhanced progression of breast cell carcinogenesis chronically-induced by PhIP. Cells co-exposed to NB and PhIP (NBP) acquired higher degrees of cancer-associated properties including enhanced induction of the epithelial-to-mesenchymal transition program and enriched stem-like cell populations compared to cells sequentially exposed to NB followed by PhIP (NB/P). Using these cancer-associated properties as targets, we demonstrated that combined green tea catechins (GTCs) were more effective than individual catechins in suppression of cellular carcinogenesis chronically induced by NBP.

Studies in Chapter 3 revealed that reactive oxygen species (ROS) and ERK pathway activation were transiently induced by NBP during each exposure. Cross-talk between reinforced ROS elevation and the ERK pathway played an essential role in increased DNA oxidation and damage which contributed to enhanced initiation of cellular carcinogenesis and led to enhanced acquisition of cancer-associated properties. Using NBP-induced transient changes and cancer-associated properties as targets, we revealed that physiologically-achievable levels of combined dietary ergosterol and mimosine were highly effective in blocking NBP-induced transient endpoints, including ROS-mediated DNA oxidation, which accounted for their ability to suppress progression of NBP-induced cellular carcinogenesis. Thus, combined dietary components such as GTCs, ergosterol and mimosine should be considered for affordable prevention of sporadic breast cancer associated with long-term exposure to environmental and dietary carcinogens.

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