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的癌症(1/8的终生确诊概率)。 随着越来越多的女性退伍军人(&gt；200万)表现出更高的确诊概率， 退伍军人管理局认识到这是一个严重的问题。大多数乳腺癌是在I-III期被诊断出来的 用细胞毒性或内分泌疗法治疗的。有害的是，这些患者有运动不耐受，这阻碍了 身体机能和生活质量。影响深远的系统性功能障碍很可能是由这些有害影响引起的 乳腺癌，细胞毒性和内分泌治疗会加重乳腺癌的发病率。这样的外周后遗症是 有希望的治疗靶点，以减轻乳腺癌的继发性影响和这些疗法引起的 运动不耐受，从而改善这些基本的抗癌疗法，并保持生活质量。因此， 我们迫切需要确定系统性功能障碍的部位和潜在机制，这一需求尚未得到满足 以及I-III期乳腺癌引起的运动不耐受以及细胞毒性和内分泌治疗。反应性 乳腺癌患者手术前/治疗前血氧/氮水平升高 正在接受细胞毒性或内分泌治疗，这可能是导致全身功能障碍的一个机制。 重要的是，外周血管、线粒体和神经肌肉系统是导致 易受ROS升高影响的健康和疾病中的运动不耐受，使这些可能的部位 乳腺癌及细胞毒性和内分泌导致运动不耐受的全身功能障碍 治疗。线粒体靶向抗氧化剂Mito-Q(Mito-Q)的最新研究进展 揭示ROS的机械性、因果作用的创新机会。此应用程序的重点是确定 部位(外周血管、线粒体和神经肌肉系统)和潜在机制(升高 ROS)导致I-III期乳腺癌(A期)引起的运动不耐受，并具有细胞毒性和 内分泌治疗(B期)。我们的中心假设是全身性血管、线粒体和 I-III期乳腺癌诱发神经肌肉功能障碍和运动不耐受并加重 通过细胞毒性和内分泌治疗，这些可以通过阻止全身ROS的增加来缓解。 因此，I-III期乳腺癌(A期)的全身效应以及细胞毒性和内分泌治疗 (B期)将由被动腿部运动(PLM)血管功能(特定)评估确定 目的1)，骨骼肌线粒体通透性肌纤维线粒体呼吸的评估 功能(特定目标2)和膝关节伸肌运动耐量结合神经电刺激 神经肌肉功能的外周/中枢疲劳评估(具体目标3)。重要的是，建议的 研究将针对CSR&D的女性退伍军人健康优先研究领域，并将导致显著的 退伍军人乳腺癌治疗的医疗保健进展，与退伍军人退伍军人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.