Intermittent food restriction prevents mammary tumors

描述（由申请人提供）：已经进行了许多尝试来鉴定预防乳腺癌和/或乳腺肿瘤（MT）发展的饮食成分。很少有研究得出结论性的发现。然而，长期热量限制一贯降低MT发病率和延长啮齿动物的潜伏期。我们发现间歇性限制/再喂养比慢性限制更大程度地阻止转基因MMTV-TGF-α小鼠中的MT发育，即，3% vs 44%的发生率（vs 77%，自由采食小鼠）。因此，限制热量的方式对MT的发展有重大影响。假设：1-间歇性限制/再喂养的保护作用由降低的血清IGF-I和瘦素以及对信号传导途径和/或增殖/凋亡的影响介导; 2-间歇性限制/再喂养的保护作用依赖于中度严重热量限制的时期，并且通过再喂养期间的热量摄入和/或营养成分来改变; 3-慢性限制和间歇性限制/再喂养的保护作用取决于肿瘤病因。在具体目标1中，将评估间歇性限制/再喂养和慢性限制对纵向和横断面方案中血清IGF-I和瘦素的影响。在具体目标2中，将确定间歇性限制/再喂养和慢性限制对乳腺组织和MT中的细胞凋亡、增殖和IGF-I和瘦素及其受体的基因表达的影响。在具体目标3中，将确定血清瘦素水平对间歇性限制/再喂养方案对MT发育的保护性应答的影响。具体目标4将确定间歇性热量限制/再喂养的保护作用是否取决于转基因小鼠的MT致癌基因和/或背景品系。我们的长期目标是建立适用于人类的营养干预策略和/或提供见解，导致化学预防剂的发展，以模仿这种保护作用。

DESCRIPTION (provided by applicant): Many attempts have been made to identify dietary components that prevent development of breast cancer and/or mammary tumors (MTs). Few studies have produced conclusive findings. However, chronic caloric restriction consistently lowers MT incidence and extends latency in rodents. We find that intermittent restriction/refeeding prevents MT development in transgenic MMTV-TGF-a mice to a greater degree than does chronic restriction, i.e., 3% vs 44% incidence (vs 77% for ad libitum-fed mice). Thus, the manner in which calories are restricted has a major impact on MT development. Hypotheses: 1- The protective effect of intermittent restriction/refeeding is mediated by decreased serum IGF-I and leptin and effects on signaling pathways and/or proliferation/apoptosis; 2-The protective effect of intermittent restriction/refeeding is dependent upon periods of moderately severe caloric restriction and is modified by caloric intake and/or nutrient composition during refeeding; 3- The protective effects of chronic restriction and intermittent restriction/refeeding are dependent upon tumor etiology. In Specific Aim 1 the effect of intermittent restriction/refeeding and chronic restriction on serum IGF-I and leptin in longitudinal and cross-sectional protocols will be assessed. In Specific Aim 2 the effect of intermittent restriction/refeeding and chronic restriction on apoptosis, proliferation, and gene expression of IGF-I and leptin and their receptors in mammary tissue and MTs will be determined. In Specific Aim 3 the effect of serum leptin levels on the protective response of intermittent restriction/refeeding regimen on MT development will be determined. Specific Aim 4 will determine if the protective effect of intermittent caloric restriction/refeeding is dependent upon the MT oncogene and/or background strain of the transgenic mouse. Our long-term objectives are to establish nutrition intervention strategies applicable to humans and/or to provide insights leading to the development of chemopreventive agents to mimic this protective effect.