Exercise Training in Transgenic Mice Is Associated with Attenuation of Early Breast Cancer Growth in a Dose-Dependent Manner

et al. (2013) Exercise Training in Transgenic Mice Is Associated with Attenuation of Early Breast Cancer Growth in a Dose-Dependent Manner. PLoS ONE 8(11): e80123. doi:10.1371/journal.pone.0080123 Exercise Training in Transgenic Mice Is Associated with Attenuation of Early Breast Cancer Growth in a Dose-Dependent Manner Jorming Goh 0 Jesse Tsai 0 Theo K. Bammler 0 Frederico M. Farin 0 Emma Endicott 0 Warren C. Ladiges 0 Alejandro Lucia, Universidad Europea de Madrid, Spain 0 1 Interdisciplinary Program in Nutritional Sciences, University of Washington, Seattle, Washington, United States of America, 2 Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America, 3 Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington , United States of America Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p#0.01), and the greater the running distance the smaller the tumor size (Pearson's r = 20.61, p#0.04, R2 = 0.38). Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p#0.05). Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = 20.77, p = 0.014) but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p#0.005). No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation. - Funding: These studies were supported in part by NIH grants R21 CA140916 and P30 AG13280, url: www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the document. Competing Interests: The authors have declared that no competing interests exist. Epidemiological studies have revealed a protective effect of physical activity on breast cancer-related mortality in women diagnosed with breast cancer [1,2], whereby increased physical activity was associated with reduced recurrence and mortality [3]. These observations consistently suggest a potential dose-dependent effect of physical activity on breast cancer outcomes. In studies involving breast cancer survivors, physical activity patterns are measured by memory recall of their latest and life-time bouts of physical activity, which is subjective and prone to recall bias. Therefore, interpretation of physical activity measurements from epidemiological studies, while meaningful, has causal limitations. In order to identify dose and mechanisms associated with physical activity-induced tumor suppression, preclinical trials utilizing animal models are necessary. Transgenic mouse models of breast cancer represent an excellent approach to dissect the mechanisms involved in exercise-induced prevention, since these models recapitulate multiple stages of breast cancer development from tumor initiation to metastasis. Hence, the effect of exercise training on any of the stages of tumor progression could hypothetically be studied. Two transgenic mouse models of mammary cancer have been reported in exercise intervention studies [4,5,6]. Treadmill running is the most common modality adopted for endurance exercise training in mice. Chronic (20 weeks) treadmill running reduced tumor volume in C3(1)/SV40 Tag mice relative to sedentary controls [4], with serum MCP-1 and IL-6 concentrations also lower in exercisetrained mice than in sedentary mice. Voluntary wheel running (20 weeks) was similar to long-term treadmill running in attenuating mammary tumor progression, but not tumor initiation, in C3(1)/ SV40 Tag mice [5]. In contrast to the anti-tumor effects presented by these studies, 9 weeks of treadmill running exacerbated mammary tumor multiplicity and reduced survival compared with sedentary controls in the p53+/2-MMTV-Wnt-1 model of mammary cancer [6]. The discrepancy in the results could be due to multiple factors. For instance, the effects of exercise training may interact with p53, Wnt and C3(1)/SV40 signaling differently, which would impact the rates of tumor growth. Also, the kinetics of tumor progression are different between the p53-deficient and C3(10/SV40 cancer models. Thus, the tumor response to exercise training may already be inherently different. Finally, differences in the duration and intensity of exercise training as well as differences in murine background strains between the studies may influence tumor outcomes. In the last decade, the scientific community has recognized the pivotal role of the tumor microenvironment in promoting tumorigenesis and tumor progression. This paradigm shift has occurred due to the appreciation that cancer is not simply a complex mass of homogenous transformed cells, but rather is comprised of a biological niche of malignant cells and other stromal cells that cross-talk and interact with one another. The complex interaction between tumors and stromal cells in the microenvironment is dynamic and influences tumor fate, either by inducing tumor cell death and dormancy or an enhancement of growth into a malignant and metastatic state. Such interactions depend on the intercellular signaling network involving various growth factors, chemokines, cytokines and other molecules secreted by stromal cells [7]. Some of the usual suspects in the stromal microenvironment include: macrophages, fibroblasts, lymphocytes, endothelial cells and adipocytes [8]. Tumor-associated macrophages (TAMs) are macrophages recruited into the tumor microenvironment and are instrumental in dictating tumor prognosis, depending on their polarization state. Macrophages activated (polarized) by Th1 cytokines associated with T-helper 1 (Th1) cells are classified as M1 macrophages, with the ability to eliminate tumor cells in vitro [9]. Mac (...truncated)