Mechanisms underlying the protective effect of exercise and weight maintenance on metastatic progression in breast cancer

项目总结/摘要 定期的身体活动或锻炼（EX）是预防乳腺癌的有效策略。 许多研究还表明，EX显着降低复发的风险，并提高生存率， 乳腺癌患者表明EX在乳腺癌幸存者的长期健康中发挥重要作用。 到目前为止，EX和减少复发之间关系的生物学机制， 改善乳腺癌的存活率还没有得到很好的理解。我们的初步数据使用 免疫活性同系4T1.2转移性乳腺肿瘤模型表明中等重量EX 稳定的小鼠导致降低的原发性肿瘤生长和转移负荷。这与 增强T细胞功能和减少髓源性抑制细胞的积累， 免疫抑制细胞在转移过程中起重要作用。因此，EX和/或重量维持（WM）可 通过预防或延迟乳腺癌患者的转移， 进展在当前的应用中，我们将确定我们的干预对肿瘤的保护作用是否 生长和转移主要是由于能量平衡的变化（例如防止体重增加）或 EX（与体重变化无关）对肿瘤结局和转移的直接影响。balb/c小鼠 将被随机分配到EX或久坐对照（SED）组，并获得转轮或对照组 在将5X104个4T1.2细胞（一种转移性肿瘤细胞系）注射到笼中之前， 第四乳腺一组SED小鼠将随意喂食（SED/AL），而一组EX小鼠将随意喂食。 体重与SED/AL组匹配。此外，EX小鼠的一个队列将被能量限制10%， 实现重量小于SED/AL组的EX/ER组。第二组SED小鼠将进行体重测定。 与EX/ER组匹配。除了定量原发性肿瘤生长和转移负荷（目标1）之外， 我们将确定EX或WM是否改变宿主的促肿瘤与抗肿瘤免疫环境（Aim 2），和/或 代谢和炎症环境（目标3）;这些介质中哪些与肿瘤生长相关， 转移性进展到目前为止，还没有研究在相关的乳腺癌中解决这些问题。 转移模型这些研究的结果将对EX的机制提供重要的见解。 和/或WM可能发挥二级和三级癌症预防作用，并通过以下方式推动该领域的发展： 研究特定的生物学途径，并为未来的实验确定目标。确定关键 将EX和/或WM与降低的转移负荷联系起来的机制可能最终使我们能够设计更多的 有效的预防和治疗策略，包括运动和体重维持干预。

PROJECT SUMMARY/ABSTRACT 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.