Epigenetics, accelerated aging, and cardiovascular health during breast cancer treatment - PROJECT SUMMARY Although survival from breast cancer (BC) has improved, BC treatment is associated with an increased risk of cardiovascular (CV) complications due in part to the cardiotoxic effects of BC treatment. BC treatments are also linked to reduced exercise capacity and cardiac function, which may contribute to the increased risk of CV events in women receiving BC treatment. Accelerated aging is one possible mechanism that could explain the declines in exercise capacity and cardiac function observed in women treated for BC. BC treatment is known to cause age-related cellular changes through multiple mechanisms including epigenetic alterations, such as DNA CpG site methylation which is a well-known marker of accelerated aging. Accelerated aging has been linked to CV disease risk and declines in cardiac function in the general population. However, no study to date has examined the association between accelerated aging and exercise capacity or cardiac function in BC patients. Identifying the mechanisms by which reduced exercise capacity and cardiac function during BC treatment occur could lead to targeted interventions. For instance, accelerometer-assessed physical activity in a healthy community-based cohort was shown to negate the effects of accelerated aging. This suggests that the rate of epigenetic age acceleration may be modified by physical activity, identifying a potential lifestyle modification to improve exercise capacity and cardiac function in BC patients. The purpose of the proposed study is to examine epigenetic changes during BC treatment and their association with changes in exercise capacity and cardiac function during BC treatment. We will utilize samples from the NCI-funded Understanding and Predicting Fatigue, CV Decline and Events after BC Treatment (UPBEAT) study, a prospective cohort of BC patients receiving cancer treatment. We will quantify DNA CpG site methylation in 100 samples of women with BC and 20 samples of non-cancer controls collected at both enrollment and 3-months after enrollment using the Illumina Infinium MethylationEPIC v2.0 BeadChip. We will characterize epigenetic changes during BC treatment compared to non-cancer controls and examine the association between epigenetic aging with changes in exercise capacity and cardiac function in women receiving BC treatment. The UPBEAT study is an ideal dataset to investigate the proposed research study as it obtained DNA specimens required to examine epigenetic changes prior to and during BC treatment, includes non-cancer controls, and has detailed data on CV risk factors, treatment data, physical activity, medications, and CV comorbidities and longitudinal data on exercise capacity and cardiac function. Findings from this study will aid in identifying mechanistic pathways in which BC treatment impacts exercise capacity and cardiac function. Understanding the role of accelerated aging in relation to exercise capacity and cardiac function in BC will provide information needed to develop targeted interventions with the long-term goal of reducing the risk of CV events in BC survivors. Additionally, this data could be used to identify BC patients at high risk of developing CV dysfunction and reduced exercise capacity, which could be used to improve risk stratification.
