A Narrowed Window for Targeting Metabolic Flexibility in Breast Cancer Prevention

乳腺癌预防中代谢灵活性的缩小窗口

• 批准号: 8606440
• 负责人: Paul S. Maclean
• 金额: $ 30.84万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606440
• 关键词: Adipose tissue; Adult; Affect; Aromatase; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Cell Proliferation; Chronic; Data; Environment; Epidemiology; Estrogens; Exercise; Exhibits; Functional disorder; Glucose; Growth; Health Care Costs; Intervention; Knowledge; Ligands; Link; Literature; Mammary Neoplasms; Mammary gland; Menopause; Metabolic; Metabolic Control; Metabolism; Metformin; Methylnitrosourea; Molecular; Nutrient; Obesity; Observational Study; Operative Surgical Procedures; Outcome; Ovarian; Ovariectomy; Overweight; Peripheral; Phenotype; Population; Postmenopause; Pre-Clinical Model; Predisposition; Prevention; Production; Progesterone Receptors; Progestins; Rattus; Regulation; Reporting; Risk; Testing; Therapeutic; Time; Tissues; Tracer; Treatment Efficacy; Tumor Burden; Tumor Promotion; Weight Gain; base; cancer risk; clinically relevant; cytokine; energy balance; flexibility; glucose uptake; high risk; improved; insight; insulin sensitivity; insulin sensitizing drugs; lipid biosynthesis; malignant breast neoplasm; neoplastic cell; novel; prevent; public health relevance; receptor; receptor expression; response; trafficking; tumor; tumor metabolism; tumor progression

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.

描述（由申请人提供）：该项目对绝经后肥胖相关风险的出现的出现进行了新的假设，同时研究了针对代谢控制，二甲双胍和定期运动的两种相关干预措施对肥胖相关肿瘤促进的影响。假设断言，肥胖相关的代谢调节与更年期诱导的体重增加的肿瘤促进作用的敏感性。基于这一假设，代谢调节受损和阳性能量失衡都是绝经后与肥胖相关的乳腺癌风险的出现所必需的。合并了三种良好特征的乳腺癌（甲硝基库），肥胖（肥胖症）和更年期（手术卵巢切除术，OVX），以创建一种实验性范例，用于研究更年期后肥胖与肥胖相关的肿瘤促进。为了响应OVX，瘦肉和肥胖，肿瘤轴承大鼠的体重增加时期，在此期间，肥胖大鼠的肿瘤较少，肿瘤的进展更多，而又更多的肿瘤新出现。肥胖大鼠的体重增加较慢，效率较低，可以预测OVX后肿瘤负担和多样性，而二甲双胍治疗可极大地抑制OVX后的肿瘤进展。肥胖中的肿瘤在OVX之前和OVX诱导的体重增加期间的表达增加。在第一个目标中，我们通过在OVX诱导的体重增加的临界窗口中操纵代谢控制和能量平衡来测试双重提取假设。在OVX诱导的体重增加的狭窄窗口中，将暂时采用已知的两种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果的影响。在第二个目的中，我们采用了24小时的能量平衡和燃料利用率研究，以检查肥胖是否会损害OVX对OVX诱导的过度喂养的代谢反应，并赋予肿瘤中“攻击性”糖酵解/脂肪生成表型。我们将检查二甲双胍治疗是否使这种代谢反应归一化，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PR表达中与肥胖相关升高的原因和后果。 AIM 2的组织将用于确定在OVX诱导的体重增加过程中响应过量喂养的乳腺中雌激素是否在局部增加。当通过富含营养或细胞因子的环境挑战时，将使用（PR+）和不（PR-）表达PR（PR-）表达PR的人乳腺癌细胞检查PR表达对肿瘤细胞代谢和增殖的非配体无关的作用。这些研究将共同​​研究，不良的代谢对照和预先存在的肿瘤受体状态是否会融合以促进卵巢功能丧失后的生存和生长。该项目中的观察结果可能指向截骨周期或更年期后不久的关键时间窗口，从而最大程度地提高了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功效。