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 #
5U54CA155850-04
Application #
8711068
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$318,879
Indirect Cost
$94,337
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Brown, Justin C; Kumar, Anagha; Cheville, Andrea L et al. (2015) Association between lymphedema self-care adherence and lymphedema outcomes among women with breast cancer-related lymphedema. Am J Phys Med Rehabil 94:288-96
Sturgeon, Kathleen; Schadler, Keri; Muthukumaran, Geetha et al. (2014) Concomitant low-dose doxorubicin treatment and exercise. Am J Physiol Regul Integr Comp Physiol 307:R685-92
Sturgeon, Kathleen M; Ky, Bonnie; Libonati, Joseph R et al. (2014) The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer. Breast Cancer Res Treat 143:219-26
Brown, Justin C; Schmitz, Kathryn H (2014) The prescription or proscription of exercise in colorectal cancer care. Med Sci Sports Exerc 46:2202-9
Brown, Justin C; Lin, Lilie L; Segal, Saya et al. (2014) Physical activity, daily walking, and lower limb lymphedema associate with physical function among uterine cancer survivors. Support Care Cancer 22:3017-25
Hammer, Sean M; Brown, Justin C; Segal, Saya et al. (2014) Cancer-related impairments influence physical activity in uterine cancer survivors. Med Sci Sports Exerc 46:2195-201
James, Peter; Berrigan, David; Hart, Jaime E et al. (2014) Effects of buffer size and shape on associations between the built environment and energy balance. Health Place 27:162-70
Brown, Justin C; Mao, Jun J; Stricker, Carrie et al. (2014) Aromatase inhibitor associated musculoskeletal symptoms are associated with reduced physical activity among breast cancer survivors. Breast J 20:22-8
Brown, Justin C; Cheville, Andrea L; Tchou, Julia C et al. (2014) Prescription and adherence to lymphedema self-care modalities among women with breast cancer-related lymphedema. Support Care Cancer 22:135-43
Schmitz, Kathryn H; Neuhouser, Marian L; Agurs-Collins, Tanya et al. (2013) Impact of obesity on cancer survivorship and the potential relevance of race and ethnicity. J Natl Cancer Inst 105:1344-54

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