THE IMPACT OF EXERCISE AND CALORIC RESTRICTION ON CANCER RECURRENCE IN MICE

了解卡路里限制和体力活动抗肿瘤作用的生物学机制，对于将这一领域的实验室进展转化为开发更有效的预防人类癌症的策略可能是至关重要的。宾夕法尼亚大学TREC生存中心项目1的目标是促进我们对能量学对乳腺癌复发的影响的理解。项目1将使用宾夕法尼亚大学开发的一种创新的乳腺癌复发基因工程小鼠模型，以确定运动、卡路里限制或两者结合对乳腺癌复发的影响。 通过依赖多西环素激活喂食高脂饮食的小鼠乳腺中与人类乳腺癌相关的癌基因，将在烤箱/蔬菜小鼠中诱发乳腺肿瘤。由此产生的肿瘤的消退将通过癌基因下调来诱导，以产生携带休眠残留肿瘤细胞的小鼠队列。携带残留疾病的超重小鼠将被随机分配到运动组、卡路里限制组和这两种干预组，或者两者都不进行，并跟踪癌症复发。 将对生物标记物进行评估，以探索能量平衡和复发之间的假设关系，包括反映PI3K-Akt-mT0R途径、胰岛素抵抗、IGF-1、HGF、脂肪因子、炎症、肿瘤血管生成和氧化应激的标记物。据我们所知，这项研究将首次在动物模型中探索运动和卡路里限制对癌症复发的影响。项目1中提出的研究建立在拟建的宾夕法尼亚大学TREC幸存者中心的研究人员在癌症生物学、肥胖症、内分泌学和运动生理学方面的独特优势和专业知识的基础上。此外，这项研究的设计与项目2中提出的类似人体试验非常相似。 聚集在一起的研究团队将共同努力创建新的实验范式，整合并超越特定学科的方法，以解决能量平衡在乳腺癌复发中的作用。通过这样做，这个项目将推进宾夕法尼亚大学TREC幸存者中心的使命，促进关于能量平衡和癌症生存的跨学科、转化科学。

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.