Energy Balance, mTOR pathway signaling, and breast cancer prognosis

项目摘要/摘要 本项目的目的是了解雷帕霉素(MTOR)途径的机械性靶点的作用 乳腺癌患者能量失衡与预后的关系及其潜在意义 靶向mTOR以抑制其激活以改善这些患者的临床结果的好处。能量 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和死亡率的潜力， 肥胖和乳腺癌预后之间的生物学机制还不完全清楚。这是至关重要的 确定全身性和中心性肥胖症的作用机制。生活方式干预可能 不适用于或不适用于所有患有乳腺癌的妇女；针对潜在的生物机制 可能会为更多的患者打开改善预后的新机会。我们建议 乳腺肿瘤中的mTOR信号通路是一种重要的靶向能量调节机制 失衡与乳腺癌预后。我们的初步数据显示，体重与体重呈线性正相关 指数和腰围与mTOR通路激活有关，如磷酸化mTOR(p- 乳腺癌患者总体和雌激素受体阴性(ER-)患者的mTOR)表达水平 肿瘤。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 活动与无病生存有关。这些数据的主要弱点是缺乏 关于治疗的信息，亚型患者的数量很少。我们将解决这些研究 我们建议的路径研究中的差距，这是一项对4,505名接受了 初发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，880例死亡，有急诊室状况的数据。我们将评估mTOR途径的活动 在肿瘤组织样本中使用10个标记的免疫组织化学小组。我们将对协会进行评估 乳房mTOR通路激活与体型(BMI、腰围、腰臀比)之间的关系 肿瘤(目标1)，并独立和联合评估mTOR通路激活与机体的关联 大小对乳腺癌预后的影响(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状况是否作为能量干预 失衡，通过mTOR通路调节影响患者预后(目标3)。我们的建议在以下方面具有创新性 使用一大组磷酸化蛋白表达，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能力。这一结果将提高我们对 在早期乳腺癌中可改变的mTOR通路激活在多大程度上可以缓解 能量失衡对乳腺癌预后的影响及其促进能量的潜力 平衡和使用mTOR抑制剂作为一种联合策略来改善临床结果。

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.