Regular physical activity or exercise (EX) is an effective strategy for primary breast cancer prevention. Numerous studies also indicate that EX significantly decreases the risk of recurrence, and improves survival in breast cancer patients suggesting an important role for EX in the long-term health of breast cancer survivors. To date, the biological mechanism(s) underlying the relationship between EX and reduced recurrence and improved survival from breast cancer are not well understood. Our preliminary data using the immunocompetent, syngeneic 4T1.2 metastatic mammary tumor model indicate that moderate EX in weight stable mice results in reduced primary tumor growth and metastatic burden. This occurs concurrently with an augmentation of T cell function and a reduction in the accumulation of myeloid derived suppressor cells, an immune suppressive cell important in the metastatic process. Thus, EX and/or weight maintenance (WM) may reduce recurrence and increase survival in breast cancer patients by preventing or delaying metastatic progression. In the current application, we will determine if the protective effect of our intervention on tumor growth and metastases is due largely to changes in energy balance (e.g. the prevention of weight gain) or to direct effect of EX (independent of changes in body weight) on tumor outcomes and metastases. BALB/c mice will be randomized to EX or sedentary control (SED) groups and given access to running wheel or control cages, respectively, for 8 weeks prior to the injection of 5X104 4T1.2 cells, a metastatic tumor cell line, into the 4th mammary gland. One cohort of SED mice will be fed ad libitum (SED/AL) and a cohort of EX mice will be weight matched to the SED/AL group. Additionally, one cohort of EX mice will be energy-restricted by 10% to achieve an EX/ER group that weighs less than the SED/AL group. A second cohort of SED mice will be weight matched to the EX/ER group. In addition to quantifying primary tumor growth and metastatic burden (Aim 1), we will determine if EX or WM alters the pro- vs. anti-tumor immune environment of the host (Aim 2), and/or the metabolic and inflammatory milieu (Aim 3); and which of these mediators are related to tumor growth and metastatic progression. To date, no studies have addressed these questions in a relevant breast cancer metastases model. Results from the studies proposed will shed critical insight on the mechanisms by which EX and/or WM may be exerting a secondary and tertiary cancer preventive effect, and move the field forward by honing in on specific biological pathways, and identify targets for future experiments. Identification of key mechanisms linking EX and/or WM to reduced metastatic burden may ultimately enable us to design more effective preventative and therapeutic strategies that include exercise and weight maintenance interventions.

Public Health Relevance

Regular physical activity reduces the risk of recurrence and improves survival from breast cancer; however, the mechanisms underlying this protective effect of exercise are unknown. Most women who die from breast cancer have metastatic disease. This project will 1) determine if exercise or weight maintenance (i.e. the prevention of weight gain) reduces tumor growth and metastatic progression in a preclinical model; 2) examine if immune, inflammatory or metabolic mediators are correlated with a reduction in tumor growth and metastatic burden; and 3) will provide critical insight as to whether exercise and/or weight maintenance may best be the best strategy to reduce recurrence and improve survival in breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA209144-01
Application #
9178613
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ross, Sharon A
Project Start
2016-08-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Sch Allied Health Professions
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802