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 pr...