Energy Balance, mTOR pathway signaling, and breast cancer prognosis

项目概要/摘要 本项目的目的是了解雷帕霉素靶点（mTOR）通路的作用机制。 能量失衡与乳腺癌患者预后之间的关系， 靶向mTOR以抑制其激活以改善这些患者的临床结局的益处。能源 失衡是影响乳腺癌预后的重要因素。虽然行为干预导致 已经显示出降低乳腺癌复发率和死亡率的潜力， 肥胖和乳腺癌结果之间的生物学机制尚不完全清楚。至关重要 确定全身性和中枢性肥胖发挥作用的机制。生活方式干预可能 并非对所有乳腺癌女性都适用或有效;针对潜在的生物学机制 可能为更多患者提供改善预后的新机会。我们建议 乳腺肿瘤中的mTOR通路信号传导是介导能量的重要且可靶向的机制 失衡与乳腺癌预后。我们的初步数据显示，体重与 指数和腰围与mTOR通路活化，如磷酸化mTOR（p- 乳腺癌患者总体和雌激素受体阴性（ER-） 肿瘤的此外，从几种磷酸化蛋白的表达来看，mTOR途径的高水平与低水平相比， 活动与无病生存有关。这些数据的主要缺点是缺乏 关于治疗的信息，亚型中的患者数量很少。我们将研究这些 我们提出的路径研究中的差距，一项前瞻性队列研究的4,505名妇女谁接受了 诊断为偶发原发性浸润性乳腺癌。在这个队列中，我们记录了571例复发，420例 第二原发性癌症和880例死亡，有ER状态数据。我们将评估mTOR通路活性， 在肿瘤组织样品中使用10标记免疫组织化学组。我们将评估协会 体型（BMI、腰围和腰臀比）与乳腺癌中mTOR通路激活之间的关系 肿瘤（目标1），并评估mTOR通路激活独立和共同与身体的关联 乳腺癌预后的大小（目标2）。为了进一步了解mTOR通路在预防中的作用， 我们将研究非肥胖、运动和二甲双胍使用的状态，作为能量干预， 不平衡，通过mTOR通路调节影响患者结果（目的3）。我们的建议是创新的， 采用一个大的磷蛋白表达面板，全面的临床和流行病学数据， ER-乳腺癌亚型的足够统计功效。研究结果将有助于我们更好地了解 在早期乳腺癌中可改变的mTOR通路激活可以减轻乳腺癌的程度。 能量失衡对乳腺癌预后的影响，并揭示了促进能量的潜力 平衡和使用mTOR抑制剂作为改善临床结果的组合策略。

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.