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A New Animal Model for Breast Cancer Development in Obese Post-Menopausal Women: Mechanism and Role of Diet
The rate of overweight and obesity has doubled over the past two decades in the United States. High body mass index (BMI) has been associated with increased risk for certain forms of cancer, including colorectal, endometrial, prostate, and postmenopausal—but not premenopausal—breast cancer. Since obesity is a major risk factor for breast cancer, developing an animal model to explore the role of obesity in breast cancer development in postmenopausal obese women is essential. The Zucker (fa/fa) rat is the best-known and most widely-used rat model for genetic obesity. However, no published study has used the 7,12-Dimethylbenz(a)anthracene (DMBA) and female Zucker rat to investigate the rate of mammary tumor development. The DMBA-induced rat mammary carcinoma model has been widely used to investigate breast carcinogenesis due to the similarity to human breast cancer. In addition, development of this model in Zucker rats will allow us to investigate the role of obesity, diet, as well as mechanisms of mammary carcinogenesis. Recently PI established the DMBA induces mammary tumors in the intact female Zucker rats. The obese rats developed 68% mammary tumors compared to only 32% of lean rats. Also obese rats developed mammary tumors at a faster rate than lean rats. Therefore the objectives of this proposal are; 1) To develop and investigate the induction of mammary tumors in absence of ovarian estrogens (as a model for post-menopausal obese women) in obese (fa/fa) rats compared to lean Zucker rats using DMBA, 2) To determine whether obese rats have different levels of enzymes responsible for the activation of DMBA to carcinogenic metabolites and 3) To determine whether dietary factors such as soy protein can protect against DMBA-induced mammary tumors in obese Zucker rats. We hypothesize that; 1) ovariectomized obese Zucker will develop mammary tumors faster and in greater in numbers than their ovariectomized lean littermates, 2) Since DMBA is a procarcinogen which requires metabolic activation by Phase I enzymes such as CYP1A1 and CYP1B1 to active carcinogen, we will investigate the role of obesity on induction of Phase I enzymes as a possible mechanism for increased mammary tumor development in obese rats and 3) we will investigate role of soy in modulation of the Phase I enzymes as a possible protective mechanism against mammary tumor development in obese rats. In summary, we will develop a rat model which will mimic post-menopausal breast cancer in obese women and investigate a possible protective mechanism by dietary manipulations.
The number of overweight Americans has doubled over the past twenty years. Women who are overweight or obese in the years after menopause have a higher chance of developing breast cancer compared to women of normal weight. In this research study, we plan to develop an animal model for breast cancer development in overweight, post-menopausal women, using rats that have a genetic change that makes them obese. We will compare breast cancer development in obese and lean rats when they are exposed to a breast cancer causing carcinogen called DMBA which is found in cigarette smoke, car exhaust and in some cooked foods. DMBA is acted on by enzymes in the body to produce more powerful carcinogens. Components of the diet as well as obesity may be able to affect the amounts of enzymes in the body that act on DMBA. The amounts of these enzymes present can determine how much DMBA is converted into more powerful carcinogens. We think that we may be able to reduce the risk of breast cancer by changing the diet, which in turn changes the levels of enzymes that act on carcinogens. The determination of how obesity affects breast cancer development in these rats will give us a new insight into how obesity can increase the risk of developing breast cancer in post-menopausal women. The results of this study will be a first step in understanding how we can prevent breast cancer from developing in post-menopausal women, possibly by changing their diets and avoiding obesity.