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 ofthe 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 oven/veight 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 ofthe Penn TREC Survivor center to promote transdisciplinary, translational science on energy balance and cancer survivorship.

Public Health Relevance

Exercise and weight control are hypothesized to reduce the risk of recurrence in cancer survivors. However, the mechanisms proposed to underlie this effect are unknown. Project 1 will use an innovative genetically engineered mouse model for breast cancer recurrence to test this hypothesis and to evaluate changes in biomarkers hypothesized to reflect causal pathways linking energy balance and recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA155850-02
Application #
8377467
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
$321,337
Indirect Cost
$93,526
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Brown, Justin C; Troxel, Andrea B; Ky, Bonnie et al. (2017) Dose-response Effects of Aerobic Exercise Among Colon Cancer Survivors: A Randomized Phase II Trial. Clin Colorectal Cancer :
Graul, Ashley; Latif, Nawar; Zhang, Xiaochen et al. (2017) Incidence of Venous Thromboembolism by Type of Gynecologic Malignancy and Surgical Modality in the National Surgical Quality Improvement Program. Int J Gynecol Cancer 27:581-587
Zhang, Xiaochen; Brown, Justin C; Paskett, Electra D et al. (2017) Changes in arm tissue composition with slowly progressive weight-lifting among women with breast cancer-related lymphedema. Breast Cancer Res Treat 164:79-88
Basen-Engquist, Karen; Alfano, Catherine M; Maitin-Shepard, Melissa et al. (2017) Agenda for Translating Physical Activity, Nutrition, and Weight Management Interventions for Cancer Survivors into Clinical and Community Practice. Obesity (Silver Spring) 25 Suppl 2:S9-S22
Igwebuike, Lotachukwu T; Zhang, Xiaochen; Brown, Justin C et al. (2017) Applying pre-participation exercise screening to breast cancer survivors: a cross-sectional study. Support Care Cancer :
Rogers, Benjamin H; Brown, Justin C; Gater, David R et al. (2017) Association Between Maximal Bench Press Strength and Isometric Handgrip Strength Among Breast Cancer Survivors. Arch Phys Med Rehabil 98:264-269
Brown, Justin C; Schmitz, Kathryn H (2017) The dose-response effects of aerobic exercise on musculoskeletal injury: a post hoc analysis of a randomized trial. Res Sports Med 25:277-289
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
Sturgeon, Kathleen M; Dean, Lorraine T; Heroux, Mariane et al. (2017) Commercially available lifestyle modification program: randomized controlled trial addressing heart and bone health in BRCA1/2+ breast cancer survivors after risk-reducing salpingo-oophorectomy. J Cancer Surviv 11:246-255

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