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    Research Grants Awarded

    Modulation Of Obesity-Induced Breast Cancer Risk By Metformin

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    It has been shown that obesity and type II diabetes are associated with an increased risk of breast cancer, particularly in post menopausal women. Chronic positive energy balance (hyperglycemia), hyper insulinemia, hypercholesterolemia and accumulation of peripheral fat deposits result in changes in the humoral (endocrine) factors, cytokines, and lipid metabolites that promote cancer, inflammation and cardiovascular disease. We hypothesize that obesity, with its deregulated glucose control and systemic adipogenesis, produces a humoral environment that stimulates mammary tumorigenesis, particularly in a post menopausal setting. To test this hypothesis and to determine whether restoration of glucose control will diminish tumor progression, we will use Wistar rats, which have a polygenetic predisposition to become obese under the same conditions that cause obesity in humans (high fat diet and limited physical exercise). Obese Prone and Obese Resistant rats will be identified using a well-established screening protocol, treated with 1-methyl-1-nitrosurea (NMU) to induce mammary tumorigenesis, and twelve weeks after treatment with NMU, all of the rats will be ovariectomized to simulate the onset of menopause. To determine whether restoration of glucose balance in the Obesity Prone rats will suppress or reverse mammary tumorigenesis, one half of the NMU-treated Obesity Prone and one half of the Obesity Resistant rats will be treated with Metformin staring one week after exposure to NMU. Metformin is an FDA approved drug for the treatment of type II diabetes and pre-diabetic syndromes, which stabilizes glucose flux, and reduces insulin resistance without the induction of hypoglycemia in patients. Tumor progression will be monitored in Metformin treated and untreated groups of Obesity Prone and Obesity Resistant rats. We will determine what cytokines and adipokines are expressed in the serum of Obese rats and whether Metformin alters the plasma levels of these factors. Changes in the levels of insulin, IGF-1, cytokines, and adipokines will be correlated with tumor incidence and biology as well as the activation of signaling molecules in the tumors themselves. The ability of serum factors to stimulate tumor cell proliferation, motility, and migration will be determined in vitro and the question of whether Metformin alters the functional and biologic properties of sera determined. The ability of plasma factors to stimulate glycolysis in vitro will also be examined. These studies will determine what humoral factors present in the plasma of Obese Prone rats stimulate mammary tumorigenesis, and whether establishment of glucose balance through the use of Metformin can alter the levels of these humoral factors and suppress or delay mammary tumorigenesis. These studies will establish preclinical data to support the administration of Metformin and related drugs in the prevention and treatment of breast cancer.

    Lay Abstract:
    There are many factors that contribute to the development of breast cancer. In order to improve the outcome for survivors and reduce the incidence of new disease it is critical for us to better understand the role of genetic factors, environmental factors and personal factors that promote breast cancer growth. Unfortunately, many of these factors interact with each other making it difficult to study them in isolation. This is the case for obesity and glucose metabolism that each appear to influence the risk of breast cancer as well as its outcome in individual patients. We know from large population based studies that overweight, post-menopausal and diabetic women are at significantly higher risk for breast cancer and if they get the disease, their disease is more aggressive. In contrast, underweight post-menopausal women have less risk for breast cancer. While the variables that might be associated with this observation are individually not well understood, it is likely that a combination of hormonal, total body fat and factors that influence the breast only (local factors) contribute to how obesity increases risk for breast cancer. It is well know that fat produces estrogen from other hormones, hence postmenopausal obese individuals have higher levels of circulating estrogen that stimulates breast cancer growth. Although we don?t understand why, the loss of glucose control that frequently occurs in obese women (either pre-diabetic syndromes or type II diabetes) further promotes breast cancer. We hypothesize that in these women fat cells and metabolic pathways produce factors which travel through the blood to stimulate breast cancer formation and growth. These complex metabolic and local factors would be extremely difficult to study in a detailed and controlled fashion in women, and therefore we have generated a rat model that appears to mimic the human condition very well. We propose to use this rat model of obesity, pre-diabetes, and induced menopause to identify and study the circulating factors in the blood and determine their role in causing breast cancer. We will also determine whether an anti-diabetic drug Metformin will reduce the risk of developing new breast cancers or suppress the growth of the tumors once they are formed. We believe that reversal of the metabolic imbalance and pre-diabetes with normalization of sugar levels and hormones in the blood will suppress the growth of obesity-related breast tumors. Blood will be collected from rats with tumors at different times during their lives to determine what factors are present. Analysis of the blood and the tumors from these rats will allow us to determine the effects of Metformin upon the development of breast tumors, as well as the molecular mechanism responsible for effects of obesity and Metformin upon breast cancer. In summary, these studies will provide important information about whether such drugs can be used effectively in women to modify breast caner risk or suppress the growth of existing breast cancers. These studies are particularly relevant to breast cancers which arise in post-menopausal women, which represent the primary population which is at risk for the disease.