TREC Grantees & Projects

Scientists at the National Cancer Institute (NCI), four research centers, and a coordination center collaborate on the Transdisciplinary Research on Energetics and Cancer (TREC) initiative to study the complex relationships between obesity, energy balance, nutrition, physical activity, and cancer risk.

Research Centers

Case Western Reserve University
Principal Investigator: Nathan Berger, M.D.
The Case Western Reserve University TREC Research concentrated on cellular mechanisms, using laboratory models and clinical research that focused on obesity, sleep and metabolic dysfunction, and colorectal cancer risk.


The overall goals of the Case Center for Transdisciplinary Research on Energetics and Cancer are defined organizationally and scientifically. Organizationally, we seek 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case Comprehensive Cancer University, 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance and their consequences relative to cancer across the continuum from cancer causation and prevention through survival, and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer.

Scientifically, we will conduct a spectrum of mechanism-based laboratory, clinical, and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects which are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities. Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of highfat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome related serum markers to understand how insulin-resistance syndrome, related genes and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on a unique population cohort followed as part of the Cleveland Children's Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as a novel and important determinant of obesity and its relation to metabolic dysfunction.

Pilot Project 1 will investigate the role of ER stress pathways Unking the metabolic stress of obesity to development of insulin resistance, its consequences and the identification of molecular targets for interrupting these pathways to prevent health consequences of obesity. Pilot Project 2 will take advantage of a unique, new metabolomic facility at Case to determine whether a metabolic signature can be identified, first in mice and then in humans, linking obesity to cancer susceptibility.

Obesity and Molecular Pathways Leading to Colon Cancer

Colon cancer is the second leading cause of cancer death in the U.S., and in the obese population the risk of developing colon cancer is elevated by 2-fold, which is among the largest increases in risk seen for any obesity associated cancer. The goals of this project are to demonstrate that increased colon cancer risk is associated with obesity per se, and not with increased dietary fat intake, to elucidate the role of increased IGF1 signaling as a mediator of the obesity associated increased colon cancer risk, and to further identify key genes whose expression within the human colon is altered by obesity and by altered IGF1 signaling. This project is based on the unique development by our group of C57bl/6 derived chromosome substituted mouse strains that are either obesity sensitive or obesity resistant when placed on a high fat diet, and also on the unique finding by our group of mutational activation of IGF1 signaling in frank colon cancers due to mutational activation of PIK3CA, an early transducer of IGF1 signaling. Our specific studies will be:

i) To compare the intestinal tumor promoting effects of high fat diet in mice that become obese on this diet (obesity sensitive) versus mice that do not develop obesity (obesity resistant), when these mice are engineered to carry the intestinal tumor inducing APC mutant Min allele.

ii) To employ expression microarrays to identify those mouse genes whose expression in the intestine is regulated by obesity, that is genes whose expression is modulated by a high fat diet only in obesity sensitive, but not in obesity resistant mice. To further identify which of these obesity regulated genes demonstrates altered expression in a microarray comparison of colonic epithelium from obese versus non-obese humans.

iii) To construct transgenic mice in which an activated mutant PIK3CA gene is specifically targeted for expression in the intestine. Further, by comparing tumor development in obese versus non-obese mice carrying this transgene, to determine whether the tumor promoting effect of activated IGF1/PIK3CA pathway signaling is epistatic with (in the same pathway with), or is independent of the tumor promoting effects of obesity.

iv) To compare the activation of IGF1 signaling in normal human colon mucosa from obese versus non-obese individuals by using quantitative immunohisochemistry to compare in these tissues the levels of phosphorylation of key IGF1 activated signaling molecules: IGF1R, AKT and mTOR. Moreover, to identify those genes whose expression in the mouse intestine is altered by increased IGF1/PI3KCA signaling, and to further identify if this "IGF1 signaling signature" of altered gene expression is evidenced on microarray comparison of gene expression in the colons of obese versus non-obese humans.

PI: Sanford Markowitz, M.D., Ph.D.

Insulin Resistance Syndrome Pathway Factors and Colon Polyps

Increasing evidence from both model systems and epidemiologic studies support that insulin resistance resulting from long-term energy imbalance plays an important role in colon carcinogenesis. The fact that the incidences of obesity, insulin resistance syndrome, and type 2 diabetes are escalating at epidemic pace worldwide makes the exploration of the insulin resistance-colon neoplasia hypothesis a subject of pressing priority. We hypothesize that candidate genes and associated biomarkers in the insulin-growth hormone-insulin-like growth factor (IGF)-insulin receptor substrate 1 (IRS-1) axis, adipogenesis pathway (adiponectin, and peroxisome proliferator-activated receptor-y), and dietary factors may work jointly to drive the development of insulin resistance syndrome, and subsequently, the development of colon adenomatous polyps, established precursors of colon cancer.

We propose a screening colonoscopy-based incident case-control study to address the insulin resistance syndromecolon polyp hypothesis by prospectively recruiting 750 incident colon polyp cases and 750 frequency-matched controls.

We will determine the candidate gene variants and haplotypes, associated biomarkers, and insulin resistance syndrome related serum markers using blood samples, and collect dietary and lifestyle risk factor information using questionnaires. We will analyze the resulting information using novel statistical models to gain comprehensive understanding of the link between insulin resistance syndrome and colon polyps. Specifically, we will 1) to investigate the impact of insulin resistance syndrome as an integral entity on colon polyps; 2) to examine the impact of candidate genes and associated biomarkers in the insulin-GH-IGF-IRS axis and adipogenesis pathway on colon polyps; 3) to evaluate the association of dietary patterns, glycemic index and glycemic load with colon polyps; and 4) to synthesize the information on candidate genes, biomarkers, and diet by looking at their joint effects on colon polyps, and to comprehensively evaluate these factors' potential direct as well as indirect (mediated by insulin resistance syndrome) impact on colon polyps.

Our study will contribute to our understanding of how insulin resistance syndrome pathway-related candidate genes and dietary factors might work in concert in the etiology of colon adenomatous polyps. Our study may have profound implication for public health prevention/intervention strategies targeting at the early stages of the colon adenoma-cancer continuum.

PI: Li Li, M.D., Ph.D.

Determinants of Obesity and Metabolic Dysfunction in Adolescents

Obesity and metabolic dysfunction increase the risk of cancer incidence and mortality. Increases in obesity and associated metabolic dysfunction are likely partly attributable to modern lifestyles characterized by high fat food intake and reduced physical activity, and such behaviors may begin in childhood. Insufficient sleep, increasingly common in adolescents, has been implicated as a risk factor for both obesity and metabolic dysfunction. In this project, we will define the relationship between a number of host risk factors operating during childhood and adolescence, including insufficient sleep and sleep apnea, to longitudinally measured changes in both weight and biochemical indices of metabolic pathways implicated in cancer. We will capitalize on access to a large population-based pediatric cohort, the Cleveland Children's Sleep and Health Study, in which multiple measures of behavioral, sleep and biochemical risk factors for obesity have been measured longitudinally. The sample includes 50% former preterm children and 41% ethnic minorities, providing opportunities to quantify and identify specific mediators of excess risk of obesity and metabolic dysfunction in vulnerable subgroups. We propose to study 600 cohort members at ages 16 to 19 years, obtaining current measures of metabolic function that have been implicated in cancer (i.e., sex hormone levels, insulin resistance, adipokines, growth factors). Anthropmetric measurements will quantify body weight, stature, and body fat distribution. Risk factor data include standardized assessments of nutritional intake and behavioral risk factors. Subjects also will undergo 5-7 day monitoring of physical activity level and sleep/wake behavior with actigraphy and an overnight sleep study. Combining these data with birth data and data collected at a previous 8 to 11 year old exam will allow us to address the hypothesis that weight gain is largest in adolescents with insufficient sleep, and such effects are independent of other behavioral risk factors; and that metabolic dysfunction is most marked in adolescents with sleep apnea and in those with rapid weight gain. Identification of risk factors for obesity and metabolic dysfunction, and their variation with demography and common behavioral factors, including the novel consideration of sleep behaviors, may help develop targeted interventions for high-risk children and elucidate important pathophysiological pathways that increase risk of several chronic health conditions, including cancer and diabetes.

PI: Susan Redline, M.D., M.P.H.

Harvard University
Principal Investigator: Frank Hu, M.D., Ph.D., M.P.H.
The Harvard TREC Research Center focuses on biological mechanisms linking obesity and cancer throughout the lifespan and at multiple levels, and translating this knowledge into actionable behavioral interventions targeting children, minorities, and cancer survivors.


In response to the National Cancer Institute re-issue of the Transdisciplinary Research on Energetics and Cancer (TREC) initiative (RFA-CA-10-006), we propose to establish a TREC Center that draws on the multidisciplinary expertise of the faculty of Harvard University at the Harvard School of Public Health (HSPH), Harvard Medical School and the Harvard-affiliated Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber/Harvard Cancer Center (DF/HCC; an NCI-designated Comprehensive Cancer Center), Harvard Pilgrim Health Care Institute, and the Harvard Center for Population and Development Studies. We have developed four complementary and interrelated research projects which are supported by four cores and additional existing resources of the participating institutions. Together, they form a cohesive, transdisciplinary center focused on the generation of new knowledge and its translation, training, and career development. In Project 1, we will examine sleep duration, energy balance, and insulin resistance among children in Project Viva; in Project 2, we will examine the relation of energetic factors (including dietary insulin demand, objectively measured energy expenditure and physical activity), sleep duration, and the built environment with novel cancer biomarkers (insulin-IGF axis, adipokines, and sex hormones) in the Nurses' Health Study; in Project 3, we will examine the relation of energetic factors (dietary insulin demand, adiposity, and physical activity) and biomarkers of the Insulin/IGF pathway with prostate cancer survivorship in the Physicians' Health Study; and in Project 4, we will conduct a randomized trial to evaluate whether a theory-based exercise intervention, alone or in combination with a pharmacological intervention, decreases circulating levels of insulin and other biomarkers previously linked to poor prognosis among colorectal cancer survivors. These projects will be supported by four cores: Administrative, Education/Training, Bioinformatics, and Developmental. Through these highly integrated projects and supporting Cores, we aim to train postdoctoral fellows and junior faculty in a transdisciplinary research environment to pursue careers in energetics and cancer and to foster innovative transdisciplinary research projects that build on the Center's and the overall TREC program's vision and resources. We have obtained strong institutional commitment, as outlined in the letters from Dr. Julio Frank, Dean of the Faculty, Harvard School of Public Health, and Dr. Edward Benz, Director of the DF/HCC and President of the Dana-Farber Cancer Institute. By leveraging multiple areas of expertise and different resources within and across TREC centers, we can help further build a unique national resource of energetics and cancer knowledge.

Sleep Duration, Childhood Energy Balance, and Insulin Resistance in Children
Childhood obesity is highly prevalent, spares no age group, and disproportionately affects racial/ethnic minority populations. Obesity in childhood is associated with adverse cardio-metabolic outcomes including hyperinsulinemia and insulin resistance which may, in turn, increase risks for many cancers. The lifecourse approach to chronic disease prevention posits that the right influences during infancy and early childhood could entrain healthful trajectories of weight and energy balance for life.

Mounting epidemiologic evidence indicates that short duration of sleep is a risk factor for obesity, insulin resistance, coronary heart disease, and all-cause mortality in adults independent of other risk factors. In addition, short-term experimental studies show that sleep restriction in adults is associated with physiologic mechanisms that may increase risk of adiposity and cardio-metabolic disorders. Yet major questions remain regarding the extent to which short sleep duration predicts adiposity and cardio-metabolic disorders in young children, and the potential mechanisms underlying these associations. Furthermore, few studies have examined the social-environmental context of early childhood sleep patterns that could inform behavioral interventions to improve sleep in high-risk groups.

The goals of this study are two-fold. The first goal is to examine associations of sleep duration - a novel risk factor for obesity and metabolic dysfunction identified in the first wave of TREC projects - in infancy and childhood with adiposity and energy balance, and with the emergence of insulin resistance and other cancer-related biomarkers in early adolescence. We will carry out this part of the project within the well-characterized pre-birth cohort study, Project Viva. This US-based study has prospectively collected and validated sleep and diet information, anthropometry, and research-quality biomarker data in children from early infancy through age 11 years. The second goal is to examine the social-cultural, behavioral, and environmental context of early childhood sleep patterns that could inform behavioral interventions to improve sleep duration and quality.

To achieve our aims, we have assembled a transdisciplinary research team of obesity and sleep medicine epidemiologists, behavioral scientists, clinical psychologists, pediatric clinical investigators, statisticians, and geneticists. The results of this study could strengthen the understanding of sleep, energy balance, and carcinogenesis from micro- (genetics) to macro- (environment) levels among children - a segment of the population at high risk for obesity and its sequelae. Furthermore, our study will supply key data needed for the design of future intervention studies, such as quantifying threshold levels of sleep that confer increased risk of obesity and metabolic dysfunction, identifying key proximate behaviors that mediate these associations, and identifying socio-cultural/environmental factors as potential targets for sleep improvement interventions.

Environmental and Lifestyle Factors, Obesity and Cancer-related Biomarkers
Disturbances in the insulin- insulin-like growth factor (IGF) axis, levels of sex hormones, and adipocytokines have been implicated in pathways connecting obesity with the development of several major cancers. However, few studies have sought to determine the origins of variation in these cancer-related biomarkers, which may be due to complex interrelationships between energetic factors such as diet, physical activity, and sleep patterns. Energetic factors may also be impacted by macro-level factors such as neighborhood social economical status (SES) and built environment. Finally, these relationships may be moderated by genetic variants, but little is known regarding this. In the first Aim, we will examine associations between energetic factors and cancer-related biomarkers in about 750 women (including 25% African American women) in the Nurses' Health Study. Energetic factors will include: (1) energy expenditure measured by doubly labeled water (DLW); (2) dietary insulin demand measured by insulin index and insulin load; (3) physical activity assessed by repeated accelerometer measurements; and (4) sleep duration assessed by two 1-week sleep logs. Cancer-related biomarkers will include (1) insulin-IGF axis components (fasting insulin, proinsulin, C-peptide, IGF-1, and IGFBP-3); (2) adipokines (total and free leptin [the ratio of leptin to soluble leptin receptor - sOB-R] and adiponectin); and (3) sex hormone-binding globulin (SHBG) and estradiol. In the second Aim, we will examine the relationships between neighborhood SES and built environment (assessed by the county sprawl index) and cancer-related biomarkers, and delineate the pathways linking these macro-level variables, energetic factors, biomarkers, and obesity. In the third Aim, we will examine whether genetic factors related to insulin resistance or insulin secretion modify the associations between behavioral (dietary insulin demand, physical activity, and sleep duration) and macro-level (neighborhood SES and built environment) factors and risk of obesity and long-term weight gain among 8,000 men and women in the Nurses' Health Study and Health Professionals Follow-up Study with available genome-wide association studies (GWAS) data. The findings from this study will not only provide insights into social, behavioral, and biological pathways underlying the relationship between energy balance and cancer risk, but also facilitate development of multi-tiered risk reduction strategies spanning diet and lifestyle modification to urban planning and community outreach for obesity and cancer prevention. Because the proposed study is based on well-established ongoing cohorts, and detailed measures of energetic factors (DLW, diet, physical activity, and sleep) and blood collection have been funded through a 2-year stimulus grant (2009-2011) by NCI, it is extremely cost-effective and timely.
PI: Frank Hu, M.D., Ph.D.

Energetic Factors, Fatal Prostate Cancer and Survivorship
In the United States, prostate cancer (PCa) is the most commonly diagnosed and second-most lethal cancer in men. Widespread prostate-specific antigen (PSA) screening has led to an increase in PCa incidence and a shift in stage at diagnosis with 90% of tumors now being localized at diagnosis. However, the determination of clinical features (PSA, clinical stage, and Gleason grade) alone has limited ability to identify patients at substantially elevated risk of PCa-specific mortality. A better understanding of the biology of lethal PCa and identification of novel markers of aggressive disease are urgently needed to develop effective therapeutic and preventive strategies. Excess body weight is consistently linked to PSA recurrence in numerous clinical studies, but its role in PCa-specific and total mortality in PCa patients remains unclear. Our intriguing preliminary findings on the relations of body mass index (BMI), C-peptide (a marker of insulin production), and adiponectin with fatal PCa support important roles of insulin/insulin-like growth factor (IGF) axis in pathways connecting energy balance and obesity to cancer progression and survival. In this application, we plan to extend this exciting work to comprehensively evaluate energetic factors and PCa-specific and all-cause mortality in men diagnosed with PCa, accounting for competing causes of death. These factors include adiposity (BMI, waist and hip circumference, and weight gain) and Type 2 diabetes (Aim 1), biomarkers (C-peptide, insulin, proinsulin, proinsulin/insulin ratio, IGF-1, IGF binding protein-3, and adiponectin; Aim 2), and genetic variants related to beta-cell function, insulin production, insulin sensitivity, and obesity identified by published genome-wide association studies (GWAS) (Aim 3). Dietary insulin demand (assessed by the C-peptide score, insulin index, and insulin load; Aim 4), vigorous physical activity and the macro-level factor of neighborhood built environment (assessed by the county sprawl index, Aim 5). This cost-effective project uses a unique and well-characterized PCa patient cohort of U.S. male physicians with 30 years of complete follow-up for outcomes and assessment of both pre- and post-cancer exposures. Findings of these studies will provide new insights for the role of energy metabolism in PCa progression, guide the identification of novel cancer therapeutic targets, and aid in the development of cancer prevention strategies from urban planning to diet and lifestyle modification.
PI: Jing Ma, M.D., Ph.D., M.P.H.

Impact of Exercise and Metformin on Hyperinsulinemia in Colorectal Cancer Survivors
Observational evidence suggests that factors related to energy balance, including exercise, body weight and diet, may be related not only to the risk of developing colorectal cancer, but also to prognosis in patients who develop the disease. One hypothesis for the impact of these factors on colorectal cancer tumorigenesis and prognosis is related to hyperinsulinemia and insulin-like growth factors. Several studies have demonstrated that colon cancer risk and recurrence rates are elevated in individuals with higher circulating levels of insulin or C-peptide as well as in individuals with higher levels of insulin-like growth factor (IGF)-I or lower levels of IGF binding protein (IGFBP)-3. However, there are no data testing strategies to lower levels of insulin or related hormones in colorectal cancer survivors. Two strategies that have strong scientific rationale to impact on the insulin-related pathways are exercise intervention and metformin. Exercise has consistently been shown in observational studies to reduce the risk of developing colorectal cancer and, more recently, risk of cancer recurrence and colorectal-cancer related mortality. Metformin reduces hyperinsulinemia and activates the AMP-activated protein kinase (AMPK) which suppresses a variety of pathways. In project 4, we propose a 2 x 2 randomized trial of supervised aerobic exercise guided by validated behavioral support techniques versus attention control and metformin versus placebo in stage l-lll colorectal cancer patients within 2 years of completion of therapy. The primary objective will be to determine whether supervised exercise training alone and metformin, either alone or in combination, can decrease fasting insulin level from baseline to 6 months in patients who completed standard therapy for stage I - III colorectal cancer. Secondary objectives include (1) comparing changes in other insulin-related biomarkers, (2) explore for an interaction effect in addition to an additive effect of exercise and metformin in reducing fasting insulin level over the 6 month intervention, (3) compare changes in body composition as well as self-directed change in diet quality, (4) compare changes in pro-inflammatory markers related to insulin resistance, (5) determine whether the theoretical constructs of the theory of planned behavior predict change in exercise behavior.
PI: Jeffrey Meyerhardt, M.D., M.P.H.

University of California, San Diego
Principal Investigator: Ruth Patterson, Ph.D., M.S.
The TREC Research Center at the University of California, San Diego focuses on mechanisms linking obesity with breast cancer risk and conducts studies investigating obesity and lifestyle factors related to insulin resistance and inflammation using mouse models, clinical trials, and wireless and networked technologies in the community.


The overall objective of the UCSD TREC Center is to assemble transdisciplinary scientific collaborators to address questions regarding insulin resistance and inflammation underlying the association of energetics with breast cancer carcinogenesis, from the cell to the community. In Project 1, we will use obese mouse models to investigate whether the beneficial anti-inflammatory and insulin-sensitizing effects of omega 3 fatty acids will reduce breast cancer tumor growth and metastasis and whether the omega 3 fatty acid receptor GPR120 is the critical mediator of those cancer-protective effects. In Project 2, we will conduct a trial in obese women to examine differential response (depending on insulin resistance status) to dietary macronutrient composition. Outcomes will include weight loss, hormonal factors, and markers of inflammation as well as nutrient-gene interactions associated with polymorphisms in IL-6 and TNF-a genes. Project 3 will investigate the degree to which metformin, a lifestyle intervention, or both, can reduce breast cancer mortality among overweight/obese, postmenopausal breast cancer survivors. We will use an innovative Biomarker Bridge design that links clinical outcomes from a breast cancer survivor cohort with intermediate outcomes from a randomized controlled trial. Project 4 will advance the science of energy expenditure estimation by using branched equation modeling techniques and artificial neural networks to analyze accelerometer and heart rate data from participants in Project 2 and 4. Global Positioning System data, which track individuals' spatial-temporal paths, combined with existing Geographic Information Systems data for San Diego County, will allow us to develop obesogenic environmental exposure estimates and relate these to metabolic risk factors. Dr. Patterson, the PI for this proposed Center, has considerable research experience in nutrition and breast cancer prevention and a strong background in leadership and management in academia and industry. The central leadership entity of the UCSD TREC Center will be the Executive Scientific Committee, composed of Project and Core leaders. This Committee, assisted by the Administrative Core, will provide scientific and operational oversight of the Shared Resources (Biostatistics & Bioinformatics and Biorepository) as well as transdisciplinary Training Program and the Developmental and cross-TREC Pilot Project Core. We believe that the TREC Center proposed herein has the potential to make significant contributions to understanding the link between obesity and breast cancer and provide insight regarding interventions with broad population impact for prevention and control of disease.

Role of Inflammation and Insulin Resistance in Mouse Models of Breast Cancer
Obesity confers increased risk for various forms of cancer. Breast, colon, and liver cancer are all increased in obese populations and the epidemiologic evidence for the obesity - breast cancer connection is compelling. One in eight women will be diagnosed with breast cancer during her lifetime. Breast cancer is strongly associated with age as incidence increases 10-fold for women age > 60 compared to women age > 50. Increased risk with age seems related to post-menopausal hormone levels as both obesity and hyperinsulinemia are associated with increased breast cancer risk only in women not on hormone replacement therapy. Metabolic Syndrome is associated with a higher incidence of aggressive triple negative breast tumors (ER-/PR-/HER2-) which is likely accelerated by ovarian hormone decline after menopause, as post-menopausal women are more susceptible to the deleterious metabolic effects of obesity including chronic inflammation and insulin resistance. Rodent studies have confirmed this relationship, showing that diet-induced obesity and high fat diets lead to increased incidence and growth of tumors in various breast cancer models. Despite this body of correlative evidence, the mechanisms of obesity-induced breast cancer risk remain poorly understood. Diet composition is an important factor as diets rich in saturated and omega 6 fatty acids (FAs) are pro-inflammatory and increase breast cancer risk, but diets rich in omega 3 FAs are anti-inflammatory and decrease cancer risk. The clinical data is less clear but meta-analyses of multiple human breast cancer risk studies suggest that the ratio of omega 6 to omega 3 FAs is a critical factor.

We have found that the beneficial anti-inflammatory and insulin-sensitizing effects of omega 3 FAs are mediated by the G-protein coupled receptor GPR120. Due to the potential link between obesity, insulin resistance and breast cancer risk in post-menopausal women, we hypothesize that GPR120 is the critical mediator of the protective effects of omega 3 FAs in breast cancer. We will test this in four specific aims that combine 1) studies using orthotopic tumor cell transplants and 2) spontaneous tumors in obese wild type (WT) and GPR120 knockout (KO) mice, ± omega 3 FA supplementation, 3) studies using orthotopic mouse and human tumor cell transplants into RAG2 KO mice, and 4) studies of metastasis using genetically marked tumor cells in obese WT and GPR120 KO mice. We hypothesize that omega 3 FAs will attenuate tumorigenesis and metastasis in WT but not GPR120 KO mice through their anti-inflammatory/insulin-sensitizing actions. This project aims to provide mechanistic depth that is complementary to aims of Projects 2 & 3.
PI: Jerrold Olefsky, M.D.

Diet Composition and Genetics: Effects on Weight, Inflammation, and Biomarkers
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 low fat diets, 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 of this study are: (1) To examine whether there is a differential weight loss response to different dietary macronutrient composition in 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) high monounsaturated 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.
PI: Cheryl Rock, Ph.D.

Obesity-related Mechanisms and Mortality in Breast Cancer Survivors
The objective of this proposed study is to investigate the degree to which metformin, a lifestyle intervention, or both, can reduce breast cancer mortality among overweight/obese, postmenopausal breast cancer survivors. We will use a "Biomarker Bridge" design that links clinical outcomes from a breast cancer survivor cohort with intermediate outcomes from a randomized controlled trial by means of a Biomarker Risk Score. Biomarker Risk Score Development: We will assay panels of interrelated biomarkers in 375 archived blood samples obtained from overweight/obese, postmenopausal women with a history of breast cancer (125 cases [breast cancer death]:250 matched controls). These Biomarkers represent proposed mechanisms by which obesity is associated with postmenopausal breast cancer: (1) alterations in the insulin-IGF axis, (2) concentrations of endogenous sex hormones, and (3) chronic inflammation. We will identify a set of markers that best predicts breast cancer mortality using conditional logistic regression models adjusted for prognostic factors. This model (i.e., Biomarker Risk Score) measures the log-odds of disease risk due to joint biomarker concentrations. Therefore this Risk Score can measure changes in log-odds due to changes in these markers in an individual and will be used to assess the clinical impact of the metformin and lifestyle intervention randomized trial. Metformin/Lifestyle Intervention Trial: We will conduct a 6-month, randomized controlled trial in 340 overweight/obese, postmenopausal breast cancer survivors. Participants will be randomized in equal numbers to (1) placebo, (2) metformin, (3) lifestyle intervention and placebo, or (4) lifestyle intervention and metformin. The lifestyle intervention will focus on reducing energy intake and increasing energy expenditure to achieve a 7% weight reduction. Biomarkers that compose the Risk Score will be assayed in fasting blood samples collected at baseline and 6 months. The degree to which each intervention changes (e.g., reduces) the Biomarker Risk Score will be used to predict changes (e.g. reductions) in breast cancer mortality. We hypothesize that metformin and lifestyle interventions will reduce breast cancer mortality and that the combination of those interventions will have an additive effect on lowering risk. In summary, this Biomarker Bridge Design will (i) develop a Biomarker Risk Score that predicts breast cancer mortality, (ii) examine how a metformin/lifestyle intervention changes this Risk Score, and (iii) thereby assess the degree to which metformin and lifestyle interventions influence the biological processes linking obesity with breast cancer mortality.
PI: Ruth Patterson, Ph.D.

Assessment of Energy Expenditure in Women with Increased Cancer Risk
Energy expenditure is a key component of energetics, and physical activity comprises the largest modifiable component of energy expenditure. Energy expenditure and physical activity are strongly related to Insulin resistance and other markers of glycemic control important for cancer risk. Sedentary behavior has also recently emerged as an independent predictor of metabolic risk, and temporal analyses of objective sedentary behavior data have indicated that breaks in sitting time may be a critical intervention strategy to complement improvements in moderate to vigorous physical activity. In the last decade, the impact of the built environment has also been assessed in relation to physical activity, sedentary behavior and weight status. This research, however, has focused on a static view of residential neighborhoods which may be confounding the relationship between health and place. We propose to advance the field of energy expenditure, physical activity, and sedentary behavior assessment across the cancer continuum by improving the accuracy of energy expenditure-related assessments in our TREC projects #2 and #3. We will use state of the art accelerometers with simultaneous heart rate recording to improve the accuracy of measuring physical activity, sedentary behavior, and energy expenditure. In addition to branched equation modeling techniques we will also use new computational approaches for analyzing data streams from these devices, including artificial neural networks that allow combining these data to decipher the frequency, intensity, duration, and type of physical activity and sedentary behavior so as to optimally characterize behaviors of study participants and reduce the measurement noise in observed relationships between these behaviors and markers of glycemic control. Finally, data from Global Positioning System devices that track the temporal and spatial movements of participants will be combined with existing Geographic Information Systems data for San Diego County to allow us to develop obesogenic environmental exposure estimates and relate these to the metabolic risk factors. These data will be processed through software developed by our group under the NIH Gene & Environment Initiative. This will enable us to use novel computational techniques to assess the relationships over time and across the study arms between energy expenditure, physical activity and sedentary behavior and metabolic risk factors related to breast cancer measured in Projects #2 and #3 as well as the moderating effect of exposure to obesogenic environments.
PI: Jacqueline Kerr, Ph.D.

University of Minnesota
Principal Investigator: Robert Jeffery, Ph.D.
The University of Minnesota TREC Research Center focused on population studies that examined the causes of, and effective prevention strategies for, obesity in youth and families.


The purpose of this center proposal is to conduct transdisciplinary research, training, and outreach on obesity and cancer in youth, family, and young adults. The proposed Center will address questions about the etiology, prevention, and treatment of obesity in youth and families, and explore biological pathways that may link obesity to cancer. The center proposal includes three specific research projects. Project 1 is a multifactorial, cross-sectional, and prospective observational study examining predictors of obesity development in adolescents, including sociocultural factors, family factors, environmental factors, and individual factors. Project 2 is a study evaluating family-base, weight-gain prevention intervention that particularly emphasizes intervention on environmental contributors to weight gain. Project 3 is a study of the effects of physical activity on estrogen metabolism, oxidative stress, and DMA repair mechanisms in young women. The three R01 grants will be supported by two cores, an Administrative Core and a Data Services and Analysis Core. The proposal also includes a career development component, substantial funding for developmental projects, and a dissemination/translation component. The overall goals are to advance transdisciplinary science in the advancement of understanding of obesity, youth, family, and cancer; to support the career development of new investigators in the field; and to disseminate scientific knowledge about the topic to broader audiences.

Etiology of Adolescent Obesity

This research will examine cross-sectional and prospective predictors of adolescent obesity using a socialecological framework. We will recruit 420 youth and one of their parents from an existing cohort of youth who are currently participating in the Minnesota Adolescent Community Cohort (MACC) study. The MACC cohort is a representative sample, drawn from 60 geopolitical units throughout the state of Minnesota, and has been followed for 4 years as part of a study examining the effects of state and local tobacco programs on youth tobacco use. Dr. Jean Forster is the Principal Investigator for this on-going study. For our TREC research, we will invite students in the MACC cohort who are 15-16 years old and live in the metro area of Minneapolis and St. Paul to be involved in this study of the etiologic factors of obesity in adolescents. We will assess potential obesogenic factors at the individual, family, school and community level by collecting data at three time points over a period of 24 months. Individual measures will include anthropometry and a variety of psychosocial, preference and behavioral assessments related to eating and activity. Family measures will include family socioeconomic status, parent weight and body composition, family meal and activity patterns, and the home food and activity environments. School level measures will include opportunities for physical activity, competitive foods, and school food and activity policies. Community-level measures will include the use of Geographical Information System (CIS) to assess obesogenic environmental factors such as the presence of walking and bike paths, convenience stores, and fast food restaurants. This research is multidisciplinary involving researchers from across four departments at the University of Minnesota (the Division of Epidemiology, School of Nursing, School of Kinesiology, and the College of Architecture and Landscape Architecture) and including scientists with a expertise in the biological sciences, exercise physiology, nutrition, the behavioral sciences, psychology, and urban planning. This research proposal is intended to be the first in a series of proposals that will include following the cohort into young adulthood to assess obesity risk and related cancers, help in directing the focus of future interventions to prevent the onset of childhood overweight and obesity in order to reduce chronic disease risk.

PI: Leslie Lytle, Ph.D.

Household Environmental Weight Gain Prevention

Obesity is a national epidemic that is widely recognized to be environmental in origin, Primary prevention interventions that address both environmental and individual-level influences on obesity are urgently needed.

The primary aim of the proposed study is to evaluate a household-level weight-gain prevention intervention that includes both environmental change and individual-level behavior change components. Four hundred forty households will be recruited and randomized to one of two groups for a 1-year period: 1) household environmental weight-gain prevention program or 2) control program that provides only general behavioral weight control recommendations The primary outcome is household-level change in body weight over the 1-year intervention period.

The household environmental weight-gain prevention program includes reduced access to television viewing via a television time-limiting device; reduced household availability of high fat/energy prepackaged foods and less frequent fast food restaurant use; and increased frequency of self-weighing with the provision of a home scale to each household. In addition, the individual-level behavioral change component targets specific eating and exercise behaviors that dovetail with the household environmental changes to promote weight control.

The intervention program format consists of 6 monthly face-to-face group meetings, 12 monthly newsletters, 6 encouragement telephone calls, and continuous access to intervention staff via telephone and email. The control group program consists of 12 monthly newsletters that provide general behavioral recommendations for weight control.

The primary outcome is household-level percent weight change measured one year following the initiation of treatment. Secondary outcomes are changes in energy intake, physical activity, television viewing time, and frequency of self-weighing. It is hypothesized that intervention households will gain significantly less weight over the 1-year intervention period than households randomized to the control group.

PI: Simone French, Ph.D.

Women in Steady Exercise Research (WISER)

It is not feasible to conduct randomized controlled exercise intervention trials with breast cancer diagnosis as the primary outcome. Therefore, it is of interest to determine whether exercise will alter physiologic outcomes associated with breast cancer incidence, including oxidative stress, estrogens, estrogen metabolism, and metabolic factors such as body fat, elevated fasting insulin, insulin resistance, alterations in plasma levels of IGF-axis proteins. We propose to examine the effects of aerobic exercise training on each of these mechanisms among young (18-30 years), pre-menopausal, eumenohrreic women in a randomized controlled trial. The primary hypothesis to be tested is whether exercise alters oxidative stress as measured by F2-lsoprostanes. The innovation of this grant stems from the concurrent measurement of cancer biomarkers, which will enable us to explore relationships between changes in these physiologic parameters that may have an important role in the exercise - cancer link. Compelling preliminary data indicate that the amount of exercise recommended for health promotion and chronic disease prevention (5 weekly 30 min sessions of moderate intensity aerobic exercise) may alter these risk factors in a manner consistent with reduced cancer risk. We will recruit 400 women and anticipate a dropout rate of 20%, for a final sample of 320 women (n=160 per group). Measurements will be made from days 7 to 10 of the participants menstrual cycle prior to randomization and at the 5th menstrual cycle after the baseline cycle. Participants will also use ovulation kits to determine whether exercise alters luteal phase length or ovulatory status. Measurements will include oxidative stress (F2-isoprostanes), estrogen metabolites, body composition (dual energy x-ray absorptiometry), insulin, glucose, and insulin resistance (HOMA index), insulin-like growth factor axis proteins (IGF-1, IGFBP-1, -2, and -3), submaximal fitness, questionnaires (injury/illness, demographics), and diet (by food frequency questionnaire).

PI: Mindy Kurzer, Ph.D., M.S.

University of Pennsylvania
Principal Investigator: Kathryn Schmitz, Ph.D., M.P.H.
The University of Pennsylvania TREC Research Center focuses on the association between energy balance and breast cancer recurrence and persistent adverse treatments effects and explores the impact of exercise and weight control interventions in cancer survivors through cost effectiveness analysis.


The overall goal of the Penn TREC Survivor Center is to improve the length and quality of cancer survivorship through establishing a sustainable transdisciplinary research, education, and outreach program that extends from 'bench to trench'. The proposed center will enhance knowledge of the causal associations of energy balance and breast cancer recurrence, from animal to human models, as well as exploring and integrating this knowledge with broad population impact at the policy level for control of obesity related adverse events among cancer survivors. Three projects are proposed. Project 1 will explore whether exercise and/or weight loss will alter breast cancer recurrence in mice and explore effects on biomarkers of mechanistic pathways hypothesized to explain these effects. Project 2 will translate project 1 biomarker findings into a human model. Intervention effects on clinical lymphedema outcomes will also be assessed in Project 2. Project 3 will assess whether exercise and/or weight loss is cost effective for breast cancer survivors with lymphedema. Organizationally, the administrative core will serve as the glue between the investigators, so that as the projects, training activities, and developmental pilots unfold, the transdisciplinary, translational nature of the center is preserved and extended. The developmental core will accelerate capacity to study effects of energetics on cancer recurrence by combining the unique strengths of our institution in obesity and cancer biology and extending the TREC initiative solidly into cancer survivorship. The education/training and outreach core will train scientists and clinicians regarding energy balance and cancer survivorship, service the dual purpose of educating health care providers regarding the unique energy balance issues in survivors and spurring interest in research on this growing population across the spectrum from basic science to clinical applications. The Penn TREC Survivor Center will leverage the considerable strengths of Penn scientific investigators and physician scientists to accelerate capacity for research on energetics, cancer recurrence and persistent adverse treatment effects as well as disseminating those findings to improve clinical care and outcomes for cancer survivors.

Impact of Exercise and Caloric Restriction on Cancer Recurrence in Mice
Understanding the biological mechanisms that underlie the anti-tumorigenic effects of calorie restriction and physical activity will likely be essential for translating laboratory advances in this field to the development of more effective strategies for preventing cancer in humans. The goal of Project 1 of the Penn TREC Survivor Center is to advance our understanding of the impact of Energetics on breast cancer recurrence. Project 1 will use an innovative genetically engineered mouse model for breast cancer recurrence developed at Penn to determine the effects of exercise, calorie restriction, or their combination on breast cancer recurrence. Mammary tumors will be induced in overweight mice by the doxycycline-dependent activation of an oncogene relevant to human breast cancer in the mammary glands of mice fed a high fat diet. Regression of the resulting tumors will be induced by oncogene down-regulation to generate cohorts of mice bearing dormant residual tumor cells. Overweight mice bearing residual disease will be randomly assigned to exercise, calorie restriction, both of these interventions, or neither and followed for cancer recurrence. Biomarkers will be evaluated to explore the hypothesized relationship between energy balance and recurrence and will include markers reflecting the PI3K-Akt-mT0R pathway, insulin resistance, IGF-1, HGF, adipokines, inflammation, tumor angiogenesis and oxidative stress. To our knowledge, this study will be the first to explore the impact of exercise and calorie restriction on cancer recurrence in an animal model. The studies proposed in Project 1 build on the unique combination of strengths and expertise in cancer biology, obesity, endocrinology, and exercise physiology among researchers in the proposed Penn TREC Survivor Center. In addition, the design of this study closely parallels an analogous human trial proposed in Project 2. The assembled team of investigators will work jointly to create new experimental paradigms that integrate and move beyond discipline-specific approaches to address the role of energy balance in breast cancer recurrence. In doing so, this project will advance the mission of the Penn TREC Survivor center to promote transdisciplinary, translational science on energy balance and cancer survivorship.
PI: Lewis Chodosh, M.D., Ph.D.

Women in Steady Exercise Research (WISER) Survivor Trial
Breast cancer survivors face dual challenges: 1) risk of recurrent disease and 2) dealing with the long term sequelae of their treatments. Facing these challenges can be burdensome, resulting in reduced quality of life. Obesity and sedentary lifestyle further complicate these issues. The goal of the WISER Survivor trial is to assess the effects of exercise and/or weight loss through caloric restriction on a common long term adverse effect of treatment (lymphedema), biomarkers for recurrence, and quality of life.

Lymphedema is a chronic, progressive, incurable condition characterized by arm swelling and negative alterations in function and appearance, as well as bothersome symptoms. It is among the more common, expensive, and feared persistent adverse breast cancer treatment effects. In our completed work, twice weekly weight-lifting reduced by half the number of incident clinical lymphedema events requiring medical care. In the proposed WISER Survivor trial we seek to assess whether adding aerobic exercise or weight loss through caloric restriction to the weight-lifting intervention further improves lymphedema clinical outcomes.

The WISER Survivor Trial will also test the effects of the exercise and weight loss interventions on the same recurrence biomarkers to be tested in the mouse model study (Project 1). The biomarkers include sex hormones, markers of inflammation, growth factors, adipokines, and oxidative stress. The innovation of these two paired projects include the novel approach of assessing effects of these interventions in the recurrence setting, as well as comparing effects on biomarkers in equivalent interventions in mice and humans. In addition, we assess effects of our energy balance interventions on a novel biomarker related to pathogenic angiogenesis. Another innovation includes a unique opportunity to assess whether changes in any of these biomarkers are correlated with clinical lymphedema outcomes. Finally, we seek to assess effects of our interventions on quality of life in breast cancer survivors with lymphedema.

Therefore, we propose a one year randomized controlled weight loss and exercise intervention trial in a multi-ethnic cohort of overweight and obese post-menopausal breast cancer survivors with clinically confirmed lymphedema. There will be four groups in this trial: exercise only, weight loss only, exercise and weight-loss combined, and a control group, with a sample size of 125 per group (total N=500).
PI: Kathryn Schmitz, Ph.D., M.P.H.

Breast Cancer-Related Lymphedema: Cost of Illness and Cost Effectiveness of Alternative Management Strategies
Breast cancer related lymphedema (BCRL), characterized by arm swelling, impaired function and bothersome symptoms, is a common, persistent, often progressive adverse event of breast cancer diagnosis and therapy, exacerbated by obesity and sedentary lifestyle. The WISER Survivor Trial (Project 2) will assess in a multi-ethnic cohort of overweight and obese post-menopausal women with BCRL the incremental clinical effectiveness (lymphedema flares, cellulitis, quality of life) of exercise only, weight loss only, and exercise and weight-loss combined compared with a usual care control group.

While BCRL incurs substantial health care costs (significant portions of which are borne by patients), reduces productivity and reduces quality of life, empirical data are sparse. Effective behavioral interventions such as exercise training and weight loss that temporize BCRL, mitigate its impact and prevent progression often are not reimbursed; third party payers rarely cover supplies required to mitigate BCRL. As a consequence, the current insurance structure perversely places breast cancer survivors at needless risk of BCRL adverse events and sequellae and may increase costs as a result of increased downstream complications (e.g., outpatient care and hospitalizations for repeated episodic lymphangitis and cellulitis; physical therapy for BRCL flares and symptomatic exacerbations). Thus, there is a compelling need to better characterize the medical economic impact of BCRL, as well as its short- and long-term health consequences.

Project 3 will; (1) assess BCRL direct medical care costs; (2) assess the incremental cost-effectiveness of the Project 2 WISER Survivor interventions; and (3) model the impact of the WISER Survivor interventions over an extended time frame. The novel methodological approaches developed to define and identify BCRL cases combining and integrating data from patient reports, administrative claims and national language queries of electronic medical records will inform criteria to identify and select BCRL patients for future studies, as well as establish the validity of alternative methods, while demonstrating the feasibility and potential value of this approach for other medical conditions.
PI: J Sanford Schwartz, M.D.

University of Southern California
Principal Investigator: Michael Goran, Ph.D.
The University of Southern California TREC Research Center explored the physiological, metabolic, genetic, behavioral, and environmental influences on obesity and cancer risk in minority children.


Overall Aim: We seek to establish a trans-disciplinary center to address the physiological, metabolic, behavioral, genetic, and environmental influences on obesity, metabolic health and cancer-risk with a focus on minority children. Leadership & Organization! The Center will be Directed by two distinguished and internationally known investigators in obesity, and cancer research (Michael I Goran, PhD &. Leslie Bernstein, PhD). Drs Goran and Bernstein will lead a coherent and synergistic program of 3 Projects, 2 Pilot Studies, 3 Research Cores, and a Training Core, each led by collaborative teams of investigators from diverse disciplines. Projects: In Project 1, we will examine ethnic differences in obesity-related metabolic risk factors for cancer in Hispanic and African American youth and the potential role of strength training as an innovative intervention for improving these risk factors. Project 2 will examine the biological and behavioral basis for the decline in physical activity during puberty in minority girls. Project 3 will examine the "built" environment and urban sprawl as risk factors for the development of obesity in children. The 2 pilot studies will: 1) develop and pilot test a community-based obesity intervention for Hispanic youth; and 2) examine the contribution of obesity to DNA methylation in the colon. Cores: An Administration Core will provide scientific leadership and oversight, and provide opportunities for new collaboration and dissemination of findings. The research studies will be supported by a Data Management and Analysis Core, and a Human Measures Core. Finally, a Training and Career Development Core will support the next generation of trans-disciplinary investigators in obesity and cancer research. Summary & Significance: We envision this application as an unprecedented opportunity to harness the vast scientific expertise at the University of Southern California. The broad trans-disciplinary theme will encompass studies of novel mechanisms that span from the patient bedside to the community curbside, so that more effective interventions in childhood and adolescence can be developed. Our overall vision is based on the concept that preventing obesity and promoting health in children will improve long-term cancer control in the population.

Obesity-Related Metabolic Risk for Cancer: Ethnicity and Response to Exercise in Minority Youth

Overall Goal: Project 1 will determine ethnic differences in body fat distribution, insulin resistance, insulin-like growth factors and binding proteins, inflammatory markers and oxidative stress in overweight African American and Hispanics children during the critical period of adolescent growth. Thereafter, we will examine the impact of strength training as a therapeutic intervention to improve these risk factors. We build upon previous work to hypothesize that hyperinsulinemia in African American youth is associated with important metabolic differences that could increase long-term cancer risk. Specific Aims: (1) To determine the contribution of body fat compartments (visceral fat, muscle fat and liver fat) and adipokines to insulin resistance in African American and Hispanic youth; (2) To examine differences in metabolic compensation to insulin resistance between African American and Hispanic youth; (3) To examine the influence of body fat, insulin resistance and ethnicity on markers of lipid peroxidation and oxidative stress, and (4) To determine the effects of a randomized strength training intervention on potential mechanistic factors linking obesity to cancer risk. Design: Crosssectional (40 African-Americans vs 40 Hispanics) and 16-week strength training program in which obese adolescents are randomly assigned to nutrition education or nutrition education plus supervised strength training. Dependent Variables: Major outcome variables include: Insulin sensitivity and insulin response to glucose by intravenous glucose tolerance test; whole body composition by (dual energy Xray absorptiometry); visceral fat, liver fat and muscle fat by magnetic resonance spectroscopy; blood draws for measures of oxidative stress, lipid peroxidaton, plasma lipids and genetic admixture; physical activity by accelerometry. Significance: Project 1 will shed new light on differences in metabolic risk factors for cancer between African Americans and Hispanics as well as their response to strength training. The contrast between African Americans and Hispanics is of particular interest because these groups share similar pre-disposition to obesity, greater insulin resistance and risk for type 2 diabetes, but for the major types of cancer, African Americans have substantially greater risk than Hispanics. Furthermore, this study will provide new information regarding the impact of strength training as an anti-obesity and anti-carcinogenic intervention in "at risk" minority adolescents.

PI: Michael Goran, Ph.D.

Insulin Resistance and Declining Physical Activity Levels in African American and Latina Girls

Overall goal: To determine physiological and psychological determinants of the decline in physical activity in Latina and African American girls during puberty. Rationale: The decline in physical activity that occurs during adolescence has been found consistently across gender, ethnicity and nationality in human studies, and across species in animal studies, suggesting a biological basis. The pubertal transition in Latina and African American girls represents a "critical period" of development in which increased insulin resistance and decreased physical activity have been noted. These "risky" metabolic and behavioral changes in this susceptible ethnic group may explain, in part, their increased risk for obesity. This pubertal decrease in physical activity also raises future risk of breast, endometrial and colon cancer. Specific aims and Approach: Aim 1 (Longitudinal Study): To determine the direct impact of pubertal insulin resistance in Latina and African American adolescent girls on physical activity, mood and meanings of physical activity across the pubertal transition from Tanner Stage 1-3. Aim 2: Tc determine how the impact of puberty induced insulin resistance on physical activity is mediated by moot and meanings of physical activity. Aim 3: To investigate ethnic differences in the impact of insulin resistance on mood, meanings of physical activity and physical activity. We will recruit 50 Latina girls and 50 African American girls 9-11 years of age at Tanner Stage 1. Yearly metabolic evaluations and quarterly accelerometry and psychosocial evaluations will be completed for a period of three years. A combination of path models and growth curve models will be used to understand the longitudinal impact of pubertal insulin resistance on mood, motivation and physical activity levels in Latina and African American girls as they mature. Central hypotheses: Pubertal insulin resistance leads to a decline in physical activity. The decline in physical activity in girls is partially biologically programmed, emanating from the "trigger" of insulin resistance, which is linked to affective determinants of physical activity including mood and energy levels, and these metabolic and psychological changes contribute to the marked decline in physical activity that occurs during puberty. This study will be the first to examine the temporal relationship between pubertal insulin resistance and the sharp decline in physical activity experienced by Latina and African American girls during puberty.

PI: Donna Spruijt-Metz, Ph.D.

Influence of Built Environments on the Development of Obesity During Childhood

Background: Growing evidence now links the built environment to physical activity, dietary quality, and obesity. The goal of this study is to assess the influence of the built environment on longitudinal changes in body mass index (BMI) in a cohort of 11,797 children from 16 communities across Southern California. This study will focus on the contributing role of neighborhood-level factors to the progression toward overweight and obesity or "obesogenic trajectories". We define these trajectories as the temporal progression toward overweight and obesity compared to age-adjusted growth curves for the cohort.

Methods: We build on over 8 yrs of measurements on 6,259 children in the DSC Children's Health Study (CHS) (ages 9-10 at enrollment, reaching 18 years at end of follow up). We will supplement this data set with 4+ years of follow up on 5,538 children in a new cohort (ages 6-7 years at recruitment with follow up until they are 11-12 years). Participants have been thoroughly characterized with annual measurements of height and weight, lung function, physical activity, baseline dietary intake, gender, race, ethnicity, and socioeconomic status (SES). CHS data will be integrated with measures of the built environment derived in a Geographic Information System. We will test the impact of the built environment and obesogenic trajectories using spatial statistics and multilevel growth curve models.

Specific Aims: (1) To assess the effects of the neighborhood built environment on obesogenic trajectories and (2) To explore whether individual (i.e., gender, race, SES) and contextual variables (i.e., air pollution) modify the association between the built environment and obesogenic trajectories.

Significance: Specific strengths of this application include the examination of the effects of the built environment on children's prospective change in weight status, direct assessment of children's weight status annually, efficient use of existing environmental and individual data, and the ability to evaluate potential differential effects across ethnicity/race on the relation between built environment and obesity. This project will identify specific variables in the built environment that significantly influence the development of obesity in children. These findings could have public health implications with respect to structuring the built environment to prevent obesity in children.

PI: Michael Jerrett, Ph.D.

Washington University in St. Louis
Principal Investigator: Graham Colditz, M.D., Dr.P.H.
The TREC Research Center at Washington University in St. Louis uses multilevel and multigenerational approaches to investigate mechanisms by which preconception diet, nutrition and built environment policies impact inactivity and how physical activity and energy balance influence body weight and carcinogenesis across the lifespan.


Drawing on the broad scientific expertise of faculty at WUSTL, and collaborators and consultants from other institutions, we propose to build on existing transdisciplinary approaches and create a center to address mechanisms of obesity and cancer, "from cell to society". We include projects that move beyond traditional risk factor-cancer associations to look at multilevel and multigenerational associations as well as the interaction of traditional cancer risk behaviors. We leverage the unique opportunity Missouri provides to study human populations given its diversity across race/ethnicity and socioeconomic status. We will delineate mechanisms by which preconception diet, nutrition and built environment policies impact inactivity and how physical activity and energy balance influence body weight and carcinogenesis across the lifecourse. Specifically we aim to:
1. Investigate in a mouse model the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in male mouse offspring;
2. Study the role of physical activity and obesity in post-prostatectomy urinary and sexual function;
3. Develop models of obesity across the life course and generations incorporating biologic, clinical and social determinants of risk and mortality, which can be applied to different cancer outcomes, using non-Hodgkin Lymphoma as the initial platform;
4. Study policies relating to nutrition and built environment that impact energy balance and obesity;
5. Train postdoctoral fellows in a transdisciplinary environment to pursue careers in energetics and cancer and expose scholars from across our university to transdisciplinary work in obesity and cancer;
6. Foster scientific synergy via smaller-scale innovative transdisciplinary research that builds on the Center's theme and resources; and
7. Maximize efficiency and productivity of TREC-related studies and cores by building an outstanding transdisciplinary center supported by outstanding administrative, budgetary, and technology resources.

To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination.

Transgenerational Animal Models of Nutritional Impact on Cancer Predisposition
The objective of the current study is to investigate the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in the male offspring. We hypothesize that a high fat maternal diet prior to and throughout pregnancy alters epigenomic marks leading to abnormal expression of key genes involved in the development of the prostate gland, which predispose the offspring to develop prostate cancer. Our rationale is that if maternal diet and metabolic bioenergetics alter the process of tumor development and progression in the prostate, then further studies exploring the mechanism of this process may elucidate new therapies and recommendations for the prevention and treatment of prostate cancer. To test our hypothesis the following aims will be pursued: Specific Aim 1: To examine prostate gland development and imprinted gene expression in control vs. high fat fed offspring, from mothers given a high fat diet for 1 month prior to conception and throughout pregnancy. Specific Aim 2: To examine the incidence and timing of tumor development in offspring of control vs. high fat fed mothers by administration of diethylstilbestrol (DES) to neonatal male mice on postnatal days 1-5. Specific Aim 3: To examine the effects of a high fat diet on tumor development in an established model for prostate cancers. The high fat diet experiment will be performed in mice with prostate specific knockout of PTEN vs. controls (Ptenloxp/loxp;PB-Cre4+) vs Pten+/+;PB-Cre4-).

This proposal is innovative in that although data show that dietary changes during pregnancy can result in epigenetic changes in the offspring and that some of these epigenetic changes have been linked to prostate cancer, the connection between maternal diet and prostate cancer has never been explored. It is anticipated that the maternal diet of high fat will accelerate this process and decrease the latency period to the development of cancer. If successful in completing our aims this work will advance our understanding of how changes in maternal diet and metabolic bioenergetics in utero have transgenerational effects on the predisposition and development of prostate cancer.
PI: Kelle Moley, M.D.

Prostatectomy, Incontinence and Erectile function (PIE)
Using supplemental data collection in two ongoing cohort studies, we will examine whether physical activity and obesity, individually and jointly, influence sexual and urinary function outcomes in men with clinically localized prostate cancer undergoing radical prostatectomy. We will explore whether these associations vary by race. Finally, we will investigate whether post-surgical change in physical activity and weight are associated with urinary and sexual function.

Aim 1: To determine the independent associations of pre-surgical physical activity and BMI with postprostatectomy urinary and sexual function.

Aim 2: To explore the additive and multiplicative effects of physical activity and BMI on sexual and urinary function.

Secondary Aim 1: To help inform potential future interventions, we will examine the effect of change in physical activity and BMI from pre-treatment to 12 months post surgery on urinary and sexual function.

Secondary aim 2: To explore whether the hypothesized effect of physical activity and BMI on urinary and sexual function differs by race.
PI: Graham Colditz, M.D., Dr.P.H. and Adam Kibel, M.D.

Worksite Policies and Neighborhood Influences on Obesity and Cancer Risk
Up to 30% of all cancer deaths in the United Slates may be attributable to obesity. Environmental and policy supports for physical activity and healthy eating represent promising strategies to curb the rise in obesity rates and related cancers. Mounting research suggests that the built environment can facilitate or constrain physical activity and healthy eating, particularly for low-income and minority populations. However, virtually all of this research has examined environmental influences among residential settings, disregarding the work environment where employed adults spend much of their time. The overall goal of this project is to understand how environments and policies where employed adults live and work are associated with obesity. This goal will be accomplished by addressing the following aims: (1) Develop and test the reliability and validity of self-reported instruments for assessing worksite environments and policies relevant for physical activity and diet behaviors; (2) Examine whether specific types and number of worksite supports for physical activity and healthy eating are predictive of obesity; (3) Examine whether perceived and objectively measured characteristics of the built environment in the residential and worksite neighborhood are independently and jointly associated with body mass index (BMI); and (4) Disseminate findings to local worksites, governments, and practitioners. Employed adults (n=2000) will be sampled among randomly selected census tracts in four metropolitan areas in Missouri, with oversampling of high racial/ethnic minority and high population density census tracts. Data on self-reported behaviors, BMI, and perceived environmental and organizational supports for physical activity and healthy eating will be derived from a targeted random-digit-dial telephone survey. Accelerometry will be collected on a sub-sample of the study population. Participants' data will be linked with contextual poverty, environmental and policy data derived using Geographic Information Systems, and multilevel modeling will be used to analyze the nested data. Findings will be disseminated among urban planners, employers, and policymakers to encourage the translation of evidence into practice and policies.
PI: James Aaron Hipp, Ph.D., B.S. and Ross Brownson, Ph.D.

Social Determinants in the Link between Obesity and Cancer
Project 4 will focus on understanding the role that social determinants play in the link between obesity and cancer at the population level across the lifespan by developing a multi-cohort simulation model of obesity and non-Hodgkin's lymphoma (NHL).

Aim 1: Develop a multi-cohort system dynamics computer simulation model of obesity and NHL population level incidence, treatment toxicity and survival trends. This will extend the obesity modeling from childhood to adult populations, develop a population level model of NHL, and based on emerging individual level analysis from the VHA cancer registry database, integrate these two models over the life course.

Aim 2: Analyze the resulting model to identify how social determinants influence obesity and NHL population level incidence and outcome trends. This analysis will identify dominant social determinants, delayed effects, and temporal relationships across the life course.

Aim 3: Design guidelines along with their implementation strategies to identify the most effective way to reduce the impact of social determinants of NHL population level outcomes. This will generate different guidelines (e.g., policy, prevention, screening, treatment, and survivorship care) along with potential implementation strategies to determine the best combination of guideline-implementation strategy for reducing the burden of NHL.

This project is transdisciplinary. It will complement existing and separately funded work to develop an innovative system dynamics model of childhood obesity by extending the model into adulthood across the lifespan and develop a NHL model that will be combined with the extended obesity model. Once established, additional cancers can be added to the model from this or other TRECs.

This project is significant. It will not only provide rigorous conceptual models of how social determinants for obesity and NHL might interact over time, but also help identify key areas for future transdisciplinary research that have high potential for population level impact. Involvement of the expert panel in the modeling process will facilitate the development of transdisciplinary knowledge. The model will also be one of the first to link efforts from the NIH funded Cancer Intervention and Surveillance Modeling Network (CISNET) and the NIH/RWJF funded Comparative Modeling (CompMod) Network for obesity prevention.
PI: Peter Hovmand, Ph.D., M.S.W. and Graham Colditz, M.D., Dr.P.H.

Coordination Center

Coordination Center (FHCRC)
Principal Investigator: Mark Thornquist, Ph.D.
Fred Hutchinson Center Research Center also served as the Coordination Center for the TREC initiative, supporting communication, dissemination, data sharing, and collaboration among the TREC Research Centers and NCI. The Coordination Center at the Hutchinson Center continues its role in the current round of the TREC initiative.


Understanding the association between energetics and cancer risk, determining its underlying mechanisms, and developing effective interventions to alter energetics to decrease cancer risk are of paramount importance in reducing cancer risk in the U.S. in the face of a rising obesity epidemic. The study of energetics and cancer requires a transdisciplinary approach to transform knowledge obtained in the laboratory and epidemiological studies into interventions that work. The charge of the Transdisciplinary Research on Energetics and Cancer (TREC) consortium is to create a cross-disciplinary team of investigators to comprehensively deal with all aspects of the energetics and cancer in order to help NCI reach its year 2015 goal of eliminating suffering and death due to cancer. The TREC Coordination Center (CC) will facilitate the transformation of knowledge among the TREC Centers and the research community at large to enhance the pace of scientific progress and help ensure that the TREC consortium is greater than the sum of its parts.

Toward this end, under the direction of the TREC Steering Committee, the CC will

1) enhance scientific interactions by identifying research commonalities across TREC sites, developing common data elements and instruments, facilitating the mapping of existing data to the common elements, training investigators as needed, and creating a data warehouse for use by both the TREC Centers and the research community;

2) support communication and dissemination of knowledge through a web site, mailing lists, organizing meetings, and creating special working groups as needed; and

3) assist the NCI program office in developing evaluation metrics to measure the TREC consortium's progress.