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

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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Article number19
JournalBreast Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Feb 21 2017

Keywords

  • Breast cancer
  • Epigenetics
  • Methylation
  • Physical activity
  • Survival

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