PROJECT SUMMARY Reduced exercise capacity is the hallmark symptom of heart failure (HF) and the primary morbidity experienced by women treated for breast cancer (BC). No established therapies exist to mitigate treatment-related declines in exercise capacity and lower HF risk in BC survivors. We found that meeting physical activity (PA) recommendations during the first 3 months of BC treatment was associated with preserved exercise capacity. Yet, nearly 80% of women were inactive during treatment. While center-based aerobic PA and/or strength training programs maintain exercise capacity during and after BC treatment, they are structured programs and typically have low adherence due to time constraints, travel barriers, persistent fatigue, and compromised immunity during BC treatment. Generalizability of these trials is limited as only the most motivated and physically active individuals enroll. Thus, there is a need for feasible and practical PA programs to engage women with BC. Recent work highlights the value of lifestyle PA to reduce HF risk by improving exercise capacity. Interventions that target lifestyle PA, such as vigorous intermittent lifestyle physical activity (VILPA), can heighten access for women with BC and attract time-limited and less physically active participants. VILPA is characterized by brief bouts of vigorous PA completed during activities of daily living and is associated with a 48% reduction in cardiovascular (CV) mortality compared to inactivity. Small amounts of VILPA (3 minutes/week) have shown improvements in exercise capacity in non-cancer populations. However, the efficacy of a VILPA solution for preserving exercise capacity in BC patients is unknown. Additionally, the mechanisms underlying PA benefits are unknown, which creates a major gap for refining PA-based interventions and maximizing efficacy. In this K99 project, prior to testing VILPA in a clinical trial (R00), I will examine mechanisms underlying the association of PA to prese