Modification of the association between recreational physical activity and survival after breast cancer by promoter methylation in breast cancer-related genes

McCullough, Lauren E.; Chen, Jia; Cho, Yoon H.; Khankari, Nikhil K.; Bradshaw, Patrick T.; White, Alexandra J.; Teitelbaum, Susan L.; Terry, Mary Beth; Neugut, Alfred I.; Hibshoosh, Hanina; Santella, Regina M.; Gammon, Marilie D.

Background: 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.

Methods: Using 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.

Results: All-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.

Conclusions: The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes.


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Also Published In

Breast Cancer Research

More About This Work

Academic Units
Environmental Health Sciences
Pathology and Cell Biology
Published Here
November 14, 2017


Keywords: Physical activity, Epigenetics, Methylation, Breast cancer, Survival