Excess adiposity is a risk factor for postmenopausal breast cancer and a major risk factor for recurrence in both pre- and postmenopausal breast cancer, and the biological mechanisms are not fully understood. Obesity is associated with elevated endogenous circulating estrogen as well as activation of the immune system, a key causative factor in insulin resistance and hyperinsulinemia. Optimal macronutrient distribution of weight loss diets has not been established. Cancer control guidelines have historically encouraged a lowfat diet, but current evidence does not suggest this strategy to be of particular benefit. Emerging evidence suggests that the optimal diet composition for weight loss may differ across individuals based on metabolic status and genetic factors. Effects of diet composition on hormonal and other factors linking obesity to breast cancer in weight loss interventions have not been compared or examined.
The specific aims ofthis study are: (1) To examine whether there is a differential weight loss response to different dietary macronutrient composition in a weight loss intervention in healthy obese women, depending on insulin resistance status; (2). To examine whether there is a differential response (depending on insulin resistance status) to different dietary macronutrient composition in a weight loss intervention in the hormonal factors and markers of inflammation that may link obesity to breast cancer mortality (insulin, SHBG, estrogens, C-reactive protein, interleukin-6 [IL-6], tumor necrosis factor a [TNF-a], and as a marker for gene expression, IL-6 and TNF-a gene methylation);and (3) To identify nutrient-gene interactions that contribute to differential response of cytokines to weight loss and diet composition associated with polymorphisms in IL-6 and TNF-a genes.
These aims will be addressed in a randomized controlled study involving 156 obese women randomly assigned to a high-carbohydrate (65% energy) low-fat (20% energy) or low-carbohydrate (45% energy) highmonounsaturated fat (35% energy) diet in a 12-month behavioral weight loss program. We hypothesize that greater weight loss and reduction in biomarkers will occur in insulin resistant women assigned to the lower carbohydrate, higher fat diet. We also hypothesize that the ability of weight loss and diet modification to decrease IL-6 and TNF-a concentrations will be influenced by polymorphisms in these genes. Results of this study will help to refine and individualize dietary guidance for optimal weight control and breast cancer prevention and will contribute to knowledge of mechanisms that link insulin resistance, inflammation and obesity to risk and progression of breast cancer.

Public Health Relevance

Excess adiposity is a risk factor for postmenopausal breast cancer incidence and mortality, and it is a major risk factor for recurrence in both pre- and postmenopausal breast cancer. Optimal diet composition for weight loss may differ across individuals based on metabolic status. Results ofthis study will help to refine and individualize dietary guidance for optimal weight control and breast cancer prevention and will contribute to knowledge of mechanisms that link insulin resistance, inflammation and obesity to breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA155435-02
Application #
8376480
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$242,752
Indirect Cost
$71,871
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
James, Peter; Hart, Jaime E; Hipp, J Aaron et al. (2017) GPS-Based Exposure to Greenness and Walkability and Accelerometry-Based Physical Activity. Cancer Epidemiol Biomarkers Prev 26:525-532
Murray, Kate; Godbole, Suneeta; Natarajan, Loki et al. (2017) The relations between sleep, time of physical activity, and time outdoors among adult women. PLoS One 12:e0182013
Kerr, Jacqueline; Marinac, Catherine R; Ellis, Katherine et al. (2017) Comparison of Accelerometry Methods for Estimating Physical Activity. Med Sci Sports Exerc 49:617-624
Rana, Brinda K; Flatt, Shirley W; Health, Dennis D et al. (2017) The IL-6 Gene Promoter SNP and Plasma IL-6 in Response to Diet Intervention. Nutrients 9:
Marinac, Catherine R; Nelson, Sandahl H; Flatt, Shirley W et al. (2017) Sleep duration and breast cancer prognosis: perspectives from the Women's Healthy Eating and Living Study. Breast Cancer Res Treat 162:581-589
Fernandez, Marina O; Sharma, Shweta; Kim, Sun et al. (2017) Obese Neuronal PPAR? Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology 158:121-133
Jankowska, Marta M; Natarajan, Loki; Godbole, Suneeta et al. (2017) Kernel Density Estimation as a Measure of Environmental Exposure Related to Insulin Resistance in Breast Cancer Survivors. Cancer Epidemiol Biomarkers Prev 26:1078-1084
Tang, Kechun; Pasqua, Teresa; Biswas, Angshuman et al. (2017) Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. J Endocrinol 232:137-153
Hartman, Sheri J; Marinac, Catherine R; Bellettiere, John et al. (2017) Objectively measured sedentary behavior and quality of life among survivors of early stage breast cancer. Support Care Cancer 25:2495-2503
Marinac, Catherine R; Nelson, Sandahl H; Breen, Caitlin I et al. (2016) Prolonged Nightly Fasting and Breast Cancer Prognosis. JAMA Oncol 2:1049-55

Showing the most recent 10 out of 40 publications