Energy Balance, mTOR pathway signaling, and breast cancer prognosis

能量平衡、mTOR 通路信号传导和乳腺癌预后

• 批准号: 10619284
• 负责人: Ting-Yuan Cheng
• 金额: $ 32.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619284
• 关键词: Address; Affect; Behavior Therapy; Biological; Body Size; Body Weight decreased; Body mass index; Cancer Prognosis; Cessation of life; Clinical; Clinical Data; Data; Diabetes Mellitus; Diagnosis; Disease; Disease-Free Survival; Estrogen Receptor Status; Estrogen receptor negative; Estrogen receptor positive; Exercise; FRAP1 gene; Gene Expression; Growth Factor; Immunohistochemistry; Intervention; Knowledge; Light; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Measures; Mediating; Mediation; Mediator of activation protein; Metformin; Mission; Newly Diagnosed; Non obese; Obesity; Operative Surgical Procedures; Outcome; Overweight; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phosphoproteins; Physical activity; Potential Energy; Prevention; Prognosis; Prospective cohort study; Recurrence; Regulation; Research; Risk; Role; Second Primary Cancers; Signal Pathway; Testing; Therapeutic; Tissue Sample; Tumor Tissue; United States National Institutes of Health; Waist-Hip Ratio; Weight; Woman; angiogenesis; breast cancer diagnosis; cancer recurrence; cancer subtypes; cell growth; cohort; energy balance; epidemiologic data; improved; inhibitor; innovation; lifestyle intervention; malignant breast neoplasm; mortality; novel strategies; primary outcome; protein expression; secondary outcome; treatment strategy; tumor; waist circumference

Project Summary/Abstract The objective of this project is to understand the role of the mechanistic Target of Rapamycin (mTOR) pathway in the association between energy imbalance and prognosis in patients with breast cancer and the potential benefits of targeting mTOR to inhibit its activation to improve clinical outcomes in these patients. Energy imbalance is an important factor affecting breast cancer prognosis. Although behavioral interventions leading to weight reduction have shown a potential to reduce breast cancer recurrence and mortality rates, the biological mechanisms between obesity and breast cancer outcomes are not entirely clear. It is crucial to identify mechanisms through which overall and central adiposity exert their effects. Lifestyle interventions may not be applicable or effective for all women with breast cancer; targeting the underlying biological mechanisms may open new opportunities to improve the prognosis for a greater number of patients. We propose that mTOR pathway signaling in breast tumors is a significant and targetable mechanism mediating energy imbalance and breast cancer prognosis. Our preliminary data show a positive linear association of body mass index and waist circumference with mTOR pathway activation, as indicated by phosphorylated mTOR (p- mTOR) expression levels, in patients with breast cancer overall and in estrogen receptor-negative (ER-) tumors. Also, from the expression of several phospho-proteins, higher vs. lower levels of mTOR pathway activities are associated with disease-free survival. The main weaknesses of these data are the lack of information on treatment, and the number of patients in subtypes is small. We will address these research gaps in our proposed Pathways Study, a prospective cohort study of 4,505 women who had received a diagnosis of incident primary invasive breast cancer. In this cohort, we have documented 571 recurrences, 420 second primary cancers, and 880 deaths with data on ER status. We will assess mTOR pathway activities using a 10-marker immunohistochemistry panel in tumor tissue samples. We will evaluate the association between body size (BMI, waist circumference, and waist-to-hip ratio) and mTOR pathway activation in breast tumors (Aim 1) and assess the association of mTOR pathway activation independently and jointly with body size on breast cancer outcomes (Aim 2). To further understand the role of the mTOR pathway in prevention, we will examine whether the status of non-obesity, exercise, and metformin use, as interventions of energy imbalance, affects patient outcomes through mTOR pathway regulation (Aim 3). Our proposal is innovative in employing a large panel of phospho-protein expression, comprehensive clinical and epidemiologic data, and adequate statistical power for ER- breast cancer subtype. The results will improve our understanding of the extent to which mTOR pathway activation, which is modifiable in early-stage breast cancer, may alleviate the influence of energy imbalance on breast cancer prognosis and shed light on the potential for promoting energy balance and using mTOR inhibitors as a combination strategy to improve clinical outcomes.

项目概要/摘要 该项目的目的是了解雷帕霉素靶点 (mTOR) 通路的作用机制 乳腺癌患者能量失衡与预后之间的关系及其潜力 以 mTOR 为靶点抑制其激活以改善这些患者的临床结果的好处。活力 失衡是影响乳腺癌预后的重要因素。尽管行为干预导致 减肥已显示出降低乳腺癌复发率和死亡率的潜力 肥胖与乳腺癌结果之间的生物学机制尚不完全清楚。至关重要的是 确定整体肥胖和中央肥胖发挥作用的机制。生活方式干预可能 不适用于或对所有患有乳腺癌的女性有效；针对潜在的生物学机制 可能为改善更多患者的预后提供新的机会。我们建议 乳腺肿瘤中的 mTOR 通路信号传导是一种重要且可靶向的能量介导机制 失衡与乳腺癌预后。我们的初步数据显示体重呈正线性相关 mTOR 通路激活的指数和腰围，如磷酸化 mTOR (p- mTOR）在乳腺癌患者和雌激素受体阴性 (ER-) 患者中的表达水平 肿瘤。此外，从几种磷酸蛋白的表达来看，mTOR 通路的水平较高与较低 活动与无病生存相关。这些数据的主要缺点是缺乏 治疗信息不详，且亚型患者数量较少。我们将解决这些研究 我们提出的 Pathways 研究中存在差距，这是一项前瞻性队列研究，对象为 4,505 名接受过 事件原发性浸润性乳腺癌的诊断。在这个队列中，我们记录了 571 例复发，420 例 第二原发癌症，以及 880 例死亡以及 ER 状态数据。我们将评估 mTOR 通路活动 在肿瘤组织样本中使用 10 标记免疫组织化学面板。我们将对协会进行评估 身体尺寸（BMI、腰围和腰臀比）与乳房 mTOR 通路激活之间的关系 肿瘤（目标 1）并独立评估 mTOR 通路激活与身体的关联 大小对乳腺癌结果的影响（目标 2）。为了进一步了解 mTOR 通路在预防中的作用， 我们将检查非肥胖、运动和二甲双胍的使用是否可以作为能量干预措施 不平衡，通过 mTOR 通路调节影响患者的治疗结果（目标 3）。我们的建议具有创新性 采用大量磷酸蛋白表达、全面的临床和流行病学数据，以及 ER-乳腺癌亚型有足够的统计功效。结果将加深我们对 mTOR 通路激活（在早期乳腺癌中是可改变的）可以在多大程度上缓解 能量不平衡对乳腺癌预后的影响并揭示促进能量的潜力 平衡并使用 mTOR 抑制剂作为改善临床结果的组合策略。