title: Modification of the association between recreational physical activity and survival after breast cancer by promoter methylation in breast cancer-related genes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Epidemiology, Emory University, Atlanta, GA, 30322, USA. lauren.mccullough@emory.edu.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McCullough
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|Department of Oncological Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Khankari
authors.affiliation: Division of Epidemiology, University of California Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bradshaw
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, 10032, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, 10032, USA.|Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.affiliation: Department of Pathology, Columbia University, New York, NY, 10032, USA.
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.affiliation: Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality* / Q000628:therapy; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015444:Exercise; D005260:Female; D006801:Humans; D008875:Middle Aged; D009026:Mortality; D009518:New York / Q000453:epidemiology; D009857:Oncogenes; D011159:Population Surveillance; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011998:Recreation; D012307:Risk Factors
keywords: Breast cancer; Epigenetics; Methylation; Physical activity; Survival