Mechanisms of systemic dysfunction responsible for exercise intolerance induced by breast cancer, cytotoxic chemotherapy, and endocrine therapy in Veterans

乳腺癌是影响美国女性的最常见癌症（1/8的终身诊断概率）。 随着越来越多的女性退伍军人（> 200万）表现出20-40%的诊断概率， 退伍军人事务部认识到这是一个严重问题。大多数乳腺癌在I-III期被诊断出来， 通过细胞毒性或内分泌疗法治疗。不利的是，这些患者有运动不耐受， 身体功能和生活质量。有害影响可能会诱发深远的全身功能障碍 乳腺癌，这是加剧细胞毒性和内分泌治疗。这样，周边，后遗症是 有希望的治疗靶点，以减轻乳腺癌的继发性影响，这些治疗引起 运动不耐症，从而改善这些基本的抗癌疗法，并保持生活质量。因此，在本发明中， 目前迫切需要确定系统功能障碍的部位和潜在机制， 以及由I-III期乳腺癌和细胞毒性和内分泌疗法引起的运动不耐受。反应性 乳腺癌患者在手术/治疗前氧/氮物质（ROS）升高， 接受细胞毒性或内分泌治疗，这可能是介导全身功能障碍的机制。 重要的是，外周血管、线粒体和神经肌肉系统是促成 运动不耐受的健康和疾病，容易受到ROS升高，使这些可能的网站， 乳腺癌和细胞毒性及内分泌引起的导致运动不耐受的全身性功能障碍 治疗最近开发的针对胆固醇的抗氧化剂米托醌（Mito-Q）提供了一种 这是一个揭示ROS的机制和因果作用的创新机会。本申请的重点是确定 位点（外周血管、线粒体和神经肌肉系统）和潜在机制（升高 ROS）导致由I-III期乳腺癌（A期）诱导的运动不耐受和细胞毒性， 内分泌治疗（B期）。我们的中心假设是，全身血管，线粒体， 神经肌肉功能障碍和运动不耐受是由I-III期乳腺癌引起的， 通过细胞毒性和内分泌疗法，这些可以通过防止系统性ROS的增加来减轻。 因此，I-III期乳腺癌（A期）和细胞毒性和内分泌治疗的全身效应 （阶段B）将通过血管功能的被动腿部运动（PLM）评估（特定 目的1）、透化肌纤维线粒体呼吸评估骨骼肌线粒体 功能（特定目标2），以及膝关节伸肌运动耐量联合电神经刺激 神经肌肉功能的外周/中枢疲劳评估（具体目标3）。重要的是，拟议的 研究将解决CSR&D的女性退伍军人健康优先研究领域，并将导致重大的 为接受乳腺癌治疗的退伍军人提供医疗保健方面的进展，与VA国家癌症战略保持一致 目的提高患者的生活质量.

Breast cancer is the most prevalent cancer affecting women in the U.S. (1/8 lifetime probability of diagnosis). With the growing number of women Veterans (>2 million) exhibiting a 20-40% greater probability of diagnosis, this a serious concern recognized by the VA. The majority of breast cancers are diagnosed in stage I-III and are treated by cytotoxic or endocrine therapies. Detrimentally, these patients have exercise intolerance that hinders physical function and quality of life. Far-reaching systemic dysfunction is likely induced by the pernicious effects of breast cancer, which are exacerbated by cytotoxic and endocrine therapies. Such, peripheral, sequelae are promising therapeutic targets to mitigate the secondary effects of breast cancer and these therapies causing exercise intolerance, thus improving these essential anticancer therapies and preserving quality of life. Thus, there is a pressing, and unmet, need to identify the sites and underlying mechanisms of systemic dysfunction and exercise intolerance induced by stage I-III breast cancer and cytotoxic and endocrine therapies. Reactive oxygen/nitrogen species (ROS) are elevated in patients with breast cancer prior to surgery/treatment and undergoing cytotoxic or endocrine therapies, which is a likely mechanism mediating systemic dysfunction. Critically, the peripheral vascular, mitochondrial, and neuromuscular systems are primary sites contributing to exercise intolerance in health and disease that are vulnerable to elevations in ROS, making these likely sites of systemic dysfunction leading to exercise intolerance induced by breast cancer and cytotoxic and endocrine therapies. The recent development of the mitochondrial-targeted antioxidant mitoquinone (Mito-Q) provides an innovative opportunity to reveal the mechanistic, causal role of ROS. The focus of this application is to determine sites (peripheral vascular, mitochondrial, and neuromuscular systems) and underlying mechanisms (elevated ROS) contributing to the exercise intolerance induced by stage I-III breast cancer (Phase A) and cytotoxic and endocrine therapies (Phase B). Our central hypothesis is that systemic vascular, mitochondrial, and neuromuscular dysfunction and exercise intolerance are induced by stage I-III breast cancer and exacerbated by cytotoxic and endocrine therapies, and these can be mitigated by preventing the increase in systemic ROS. Accordingly, the systemic effects of stage I-III breast cancer (Phase A) and cytotoxic and endocrine therapies (Phase B) will be determined by the passive leg movement (PLM) assessment of vascular function (Specific Aim 1), permeabilized muscle fiber mitochondrial respiration assessment of skeletal muscle mitochondrial function (Specific Aim 2), and knee-extensor exercise tolerance combined with electrical nerve stimulation peripheral/central fatigue assessment of neuromuscular function (Specific Aim 3). Importantly, the proposed research will address a Women Veteran’s health priority research area of CSR&D and will lead to significant advances in healthcare for Veterans treated for breast cancer, aligning well with the VA National Cancer Strategy objective to improve quality of life of patients.