Academic Commons


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.


  • thumnail for 13058_2017_Article_811.pdf 13058_2017_Article_811.pdf application/pdf 523 KB Download File

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

Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.