Abstract
BackgroundMechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality.MethodsUsing a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions.ResultsAll-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40–0.80), CCND2 (HR 0.56, 95% CI 0.32–0.99), HIN (HR 0.55, 95% CI 0.38–0.80), and TWIST1 (HR 0.28, 95% CI 0.14–0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation.ConclusionsThe improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes.
Highlights
Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role
In a population-based sample of women diagnosed with first primary breast cancer, we aimed to understand whether the association between prediagnostic recreational physical activity (RPA) and all-cause or breast cancer-specific mortality was modified by gene promoter methylation in a panel of 13 breast cancer-related genes (APC, BRCA1, CCND2, CDH1, DAPK1, ESR1, GSTP1, HIN1, CDKN2A, PGR, RARβ, RASSF1A, and TWIST1) measured in tumor tissue
Associations between RPA and all-cause and breast cancer-specific mortality In Table 2, we provide effect estimates for the association between prediagnostic lifetime RPA and mortality after approximately 15 years of follow-up among our Long Island Breast Cancer Study Project (LIBCSP) cohort of 1254 women newly diagnosed with first primary breast cancer in 1996–1997
Summary
Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality. Women who engage in physical activity prior to the diagnosis of breast cancer have better overall survival than those who do not [2], but the mechanisms of this association are unknown. DNA methylation is the most extensively studied epigenetic modification and involves the addition or removal of methyl (-CH3) groups at CpG dinucleotides that influence gene regulation [4]. Interactions between the environment and DNA methylation may, inform prognostic outcomes among women diagnosed with breast cancer
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