Abstract
Simple SummaryWhile physical activity has been associated with reduced cancer risk, it is not well understood why this is the case. One possible reason is that physical activity affects DNA methylation—a process that functions to turn certain genes “on” or “off”—which can affect cancer-related processes in the body. We tested this in an experimental study, where women aged 30–45 were randomly assigned to complete 16 weeks of exercise of varying intensity and duration. We hypothesized that higher levels of exercise would lead to changes in DNA methylation that would be associated with reduced cancer risk. Contrary to our hypotheses, we found that the total amount of exercise completed was not associated with changes in DNA methylation, though we did find that increases in VO2max, a marker of physical fitness, were associated with decreases in methylation of the BRCA1 gene, and higher levels of exercise during a follow-up period were associated with lower levels of methylation of the GALNT9 gene. This study provides preliminary evidence that increased exercise behavior or fitness may affect the methylation of some genes that are related to breast cancer.Emerging research suggests that one mechanism through which physical activity may decrease cancer risk is through its influence on the methylation of genes associated with cancer. The purpose of the current study was to prospectively test, using a rigorous experimental design, whether aerobic exercise affects DNA methylation in genes associated with breast cancer, as well as whether quantity of exercise completed affects change in DNA methylation in a dose–response manner. 276 women (M age = 37.25, SD = 4.64) were recruited from the Denver metro area for a randomized controlled trial in which participants were assigned to a supervised aerobic exercise program varying in a fully crossed design by intensity (55–65% versus 75–85% of VO2max) and duration (40 versus 20 min per session). DNA methylation was assessed via blood samples provided at baseline, after completing a 16-week supervised exercise intervention, and six months after the intervention. 137 participants completed the intervention, and 81 had viable pre-post methylation data. Contrary to our hypotheses, total exercise volume completed in kcal/kg/week was not associated with methylation from baseline to post-intervention for any of the genes of interest. An increase in VO2max over the course of the intervention, however, was associated with decreased post-intervention methylation of BRCA1, p = 0.01. Higher levels of self-reported exercise during the follow-up period were associated with lower levels of GALNT9 methylation at the six-month follow-up. This study provides hypothesis-generating evidence that increased exercise behavior and or increased fitness might affect methylation of some genes associated with breast cancer to reduce risk.
Highlights
In 2020, an estimated 276,480 women will be diagnosed with breast cancer, and 42, 170 will die from breast cancer [1]
For AURKA methylation, there was a significant linear effect such that methylation increased over time, b = 0.33, 95% C.I. [0.02, 0.64], p = 0.04, and no significant quadratic effect
These results suggest that exercise is associated with healthy changes in methylation for AURKA and BCAR1 that persist after the intervention formally ended
Summary
In 2020, an estimated 276,480 women will be diagnosed with breast cancer, and 42, 170 will die from breast cancer [1]. Physical activity has been associated with a reduced risk of developing many cancers including cancer of the breast [2,3,4,5,6], but the exact biological mechanisms are not completely understood [7,8]. One promising hypothesis is that physical activity may decrease cancer risk via its influence on the methylation of genes associated with cancer [9,10]. These CpG “islands” are unmethylated or have low levels of methylation In cancer, this healthy state is disrupted, such that higher levels of methylation may silence the action of tumor suppressor genes that prevent the proliferation of cells that characterizes tumor development [11,12,13,14,15,16]. Hypermethylation of Toll-like receptor genes (e.g., TLR4 and TLR6) associated with inflammation (a cancer-related process [19,20,21]) and breast cancer cell survival/proliferation can reduce their expression, reducing the inflammatory signaling associated with chronic illness and tumor cell survival [22,23]
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