Primary interests of the Nutrition and Metabolism section are the effects of body weight and food intake on the development of breast cancer using mouse models. Past studies have included effects of genetic and dietary-induced obesity on breast/mammary tumor development particularly with respect to body fat and serum IGF-I, leptin and adiponectin levels. Other studies have assessed the impact of calorie restriction on the prevention of mammary tumors in several transgenic mice models. Of particular interst, we consistently find that periods of moderately severe calorie restriction followed by refeeding, which we term intermittent calorie restriction, results in much greater reduction in mammary tumor incidence than does the same degree of restriction implemented chronically with both interventions resulting in 20-25% calorie reduction. Mechanisms of the protective effect of caloric restriction on cancer development include studies of leptin/leptin receptors, adiponectin/adiponectin receptors and the IGF-axis. Based on results of our studies, we have hypothesized that the altered, i.e., reduced adiponectin:leptin ratio associated with obesity, provides a permissive environment for tumor development. In contrast, the reductions of IGF-I and leptin and increased adiponectin:leptin ratio resulting from periods of calorie restriction in the intermittent restriction protocol results in reduced mammary tumor development and decreased mammary tumor incidence in comparison to ad libitum fed mice as well as in the mice that are chronically calorie restricted. These studies have been expanded by Dr. Michael Grossmann to include the interaction of an omega-3 fatty acid in combination with intermittent calorie restriction on the development of mammary tumors in a project funded by Susan G. Komen for the Cure. This study uses a model of breast cancer that was previously found to be only partially responsive to the intermittent calorie restriction protocol. Further, there have been reports that omega-3 fatty acids may have cancer preventing action but the published results have not been consistent. Initial results indicate that the combination of omega-3 fatty acid and intermittent calorie restriction is more protective than the restricted protocol using omega-6 fatty acid.
We have also investigated the effects of intermittent restriction intervention in a model for prostate cancer, TRAMP mice. This intervention also protected against prostate cancer development as reflected by a delay in the initial detection of the disease as well as a later age at death.
Furthermore, the intermittent restriction appears to be far superior to chronic calorie restriction, which had little effect on prevention of prostate cancer in TRAMP mice. We have also assessed the effects of obesity on the development of prostate cancer. Our initial goal was to study the effects of obesity initiated at different ages on the development of prostate cancer using the TRAMP model. However, there were technical difficulties inducing the obesity with the chemical agent we were using. We have now completed a diet-induced obesity study in the TRAMP mice. The results indicate that obesity is associated with more severe disease which is similar to what has been reported for humans. Our most recent work focuses on the potential effect of the diabetic treatment drug metformin on mammary tumor development. This study will be conducted in a transgenic mouse model to mimic postmenopausal breast cancer and will include obese as well as normal weight subjects. We will also directly compare the effects of metformin to calorie restriction. We are also planning to undertake studies related to the effects of metformin on cancer progression.
Other Professional Activities
Margot P. Cleary
University of Miami Sylvester Comprehensive Cancer Center
University of Minnesota Masonic Cancer Center
AACR 10th Annual Frontiers in Cancer Prevention Meeting – Boston, MA
AICR Annual Research Conference – Washington, DC
AACR Annual Meeting – Chicago, IL
NIH Study Section Meeting