A Narrowed Window for Targeting Metabolic Flexibility in Breast Cancer Prevention

描述（由申请人提供）：该项目测试了一种关于绝经后出现肥胖相关乳腺癌风险的新假设，同时检查了两种针对代谢控制的相关干预措施（二甲双胍和定期锻炼）对肥胖相关肿瘤促进的影响。该假说认为，肥胖相关的代谢调节受损建立了对绝经诱导的体重增加的肿瘤促进作用的易感性。基于这一假设，代谢调节受损和正能量失衡都是绝经后出现肥胖相关乳腺癌风险所必需的。将乳腺癌（甲基亚硝基脲）、肥胖（肥胖倾向大鼠）和绝经（手术卵巢切除术，OVX）的三种充分表征的模型合并，以创建用于研究绝经后肥胖相关肿瘤促进的实验范例。响应于OVX，瘦的和肥胖的荷瘤大鼠表现出一段时间的快速体重增加，在此期间，肥胖大鼠具有较少的肿瘤消退，更多的肿瘤进展，和更多的肿瘤新出现。肥胖大鼠体重增加较慢，能量效率较低，可预测OVX后肿瘤负荷和多样性，二甲双胍治疗可显著抑制OVX后肿瘤进展。肥胖者的肿瘤在OVX前和OVX诱导的体重增加期间孕酮受体（PR）的表达增加。在第一个目标中，我们通过在OVX诱导的体重增加的关键窗口期间操纵代谢控制和能量平衡来测试双重需求假设。在OVX诱导的体重增加的窄窗期间，将短暂采用两种已知可改善代谢控制的相关干预措施（二甲双胍、定期运动），以评估其对长期肿瘤结局的影响。在第二个目标中，我们采用了24小时的多示踪剂研究的能量平衡和燃料利用，以检查肥胖是否损害代谢反应OVX诱导的过度喂养，并赋予一个“积极的”糖酵解/脂肪生成表型的肿瘤。我们将检查二甲双胍治疗是否使这种代谢反应正常化，并改善肥胖对肿瘤代谢的影响。在第三个目标中，我们研究了肥胖相关的PR表达升高的原因和后果。目标2的组织将用于确定在OVX诱导的体重增加期间，乳腺中的雌激素是否因过度喂养而局部增加。人乳腺癌细胞，做（PR+）和不（PR-）表达PR将被用来检查配体独立的影响PR表达肿瘤细胞代谢和增殖，当挑战与营养丰富或富精氨酸的环境。总之，这些研究将检查代谢控制不良和预先存在的肿瘤受体状态是否会在卵巢功能丧失后促进生存和生长。本项目中的观察结果可能指向围绝经期或绝经后不久的关键时间窗口，这将最大限度地提高改善胰岛素敏感性和/或代谢控制的干预措施的预防和治疗效果。

DESCRIPTION (provided by applicant): This project tests a novel hypothesis regarding the emergence of obesity-associated risk for breast cancer after menopause, while examining the impact of two relevant interventions targeting metabolic control, metformin and regular exercise, on obesity-associated tumor promotion. The hypothesis asserts that obesity- associated impaired metabolic regulation establishes a susceptibility to the tumor promoting effects of the menopause-induced weight gain. Based upon this hypothesis, both impaired metabolic regulation and the positive energy imbalance are required for the emergence of obesity-associated breast cancer risk after menopause. Three well-characterized models of breast cancer (methylnitrosourea), obesity (obesity-prone rats) and menopause (surgical ovariectomy, OVX) were merged to create an experimental paradigm for studying obesity-associated tumor promotion after menopause. In response to OVX, lean and obese, tumor bearing rats exhibit a period of rapid weight gain, during which obese rats have fewer tumors regress, more tumors progress, and more tumors newly emerge. The slower, less energetically efficient weight gain of obese rats predicts post-OVX tumor burden and multiplicity, and metformin therapy dramatically suppresses tumor progression after OVX. Tumors in the obese have increased expression of progesterone receptor (PR) prior to OVX, and during OVX-induced weight gain. In the first aim, we test the dual-requirement hypothesis by manipulating metabolic control and energy balance during the critical window of OVX-induced weight gain. Two relevant interventions known to improve metabolic control (metformin, regular exercise) will be employed transiently during the narrow window of OVX- induced weight gain, to assess their impact on long term tumor outcomes. In the second aim, we employ a 24-hr multi-tracer study of energy balance and fuel utilization to examine if obesity impairs the metabolic response to OVX-induced overfeeding and imparts an "aggressive" glycolytic/lipogenic phenotype in tumors. We will examine if metformin therapy normalizes this metabolic response and ameliorates the effects of obesity on tumor metabolism. In the third aim, we investigate the cause and consequences of the obesity-associated elevation in PR expression. Tissues from aim 2 will be used to determine if estrogens are increased locally in the mammary gland in response to overfeeding during OVX-induced weight gain. Human breast cancer cells that do (PR+) and do not (PR-) express PR will be used to examine the ligand-independent effects of PR expression on tumor cell metabolism and proliferation, when challenged with a nutrient-rich or cytokine-rich environment. Together, these studies will examine if poor metabolic control and pre-existing tumor receptor status converge to promote survival and growth after the loss of ovarian function. Observations in this project may point to a critical window of time in peri-menopause or shortly after menopause that will maximize the prevention and therapeutic efficacy of interventions that that improve insulin sensitivity and/or metabolic control.