Abstract
Purpose
To examine DNA methylation as a mechanism linking diet, physical activity, weight status, and breast cancer risk.
Methods
Insufficiently active women of varying weight status, without a history of cancer, completed a maximal exercise test, clinical measurement of height and weight, and a dietary intake measure. They also provided blood samples, which were analyzed to ascertain average methylation of candidate genes related to breast cancer (BRCA1, RUNX3, GALNT9, and PAX6) and inflammation (TLR4 and TLR6).
Results
Elevated weight status (r = − .18, p < .05) and poorer aerobic fitness (r = .24, p < .01) were each associated with decreased methylation of inflammation genes. Methylation of inflammation genes statistically mediated the relationship between weight status and cancer gene methylation (standardized indirect effect = .12, p < .05) as well as between cardiorespiratory fitness and cancer gene methylation (standardized indirect effect = − .172, p < .01). However, recent dietary behavior was not associated with methylation of either inflammation or cancer genes.
Conclusions
Both weight status and cardiovascular fitness are associated with methylation of genes associated with both inflammation and cancer. Methylation of inflammatory genes might serve as a mechanistic link between lifestyle factors and methylation changes in genes that increase risk for breast cancer.
References
Howlader N, Noone AM, Krapcho M et al (2011) SEER cancer statistics review, 1975–2009 (vintage 2009 populations). National Cancer Institute, Bethesda
Ogden CL, Carroll MD, Fryar CD, Flegal KM (2015) Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS Data Brief 219:1–8
Ligibel JA, Alfano CM, Courneya KS et al (2014) American society of clinical oncology position statement on obesity and cancer. J Clin Oncol 32:3568–3574. https://doi.org/10.1200/JCO.2014.58.4680
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 348:1625–1638
Park J, Morley TS, Kim M et al (2014) Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol 10:455–465. https://doi.org/10.1038/nrendo.2014.94
Aljadani HM, Patterson A, Sibbritt D et al (2013) Diet quality, measured by fruit and vegetable intake, predicts weight change in young women. J Obes. https://doi.org/10.1155/2013/525161
He K, Hu FB, Colditz GA et al (2004) Changes in intake of fruits and vegetables in relation to risk of obesity and weight gain among middle-aged women. Int J Obes 28:1569–1574. https://doi.org/10.1038/sj.ijo.0802795
Key TJ, Allen NE, Spencer EA, Travis RC (2002) The effect of diet on risk of cancer. Lancet 360:861–868. https://doi.org/10.1016/S0140-6736(02)09958-0
Steinmetz KA, Potter JD (1996) Vegetables, fruit, and cancer prevention. J Am Diet Assoc 96:1027–1039. https://doi.org/10.1016/S0002-8223(96)00273-8
Monninkhof EM, Elias SG, Vlems FA et al (2007) Physical activity and breast cancer: a systematic review. Epidemiology 18:137–157
Lynch BM, Neilson HK, Friedenreich CM (2010) Physical activity and breast cancer prevention. Physical activity and cancer. Springer, New york, pp 13–42
Dimeo FC, Stieglitz R, Novelli-Fischer U et al (1999) Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer 85:2273–2277
Ibrahim EM, Al-Homaidh A (2011) Physical activity and survival after breast cancer diagnosis: meta-analysis of published studies. Med Oncol 28:753–765
Font-Burgada J, Sun B, Karin M (2016) Obesity and cancer: the oil that feeds the flame. Cell Metab 23:48–62. https://doi.org/10.1016/j.cmet.2015.12.015
Tobias DK, Akinkuolie AO, Chandler PD et al (2017) Markers of inflammation and incident breast cancer risk in the Women’s health study. Am. J, Epidemiol
Woods JA, Vieira VJ, Keylock KT (2009) Exercise, inflammation, and innate immunity. Immunol Allergy Clin North Am 29:381–393. https://doi.org/10.1016/j.iac.2009.02.011
Calder PC, Ahluwalia N, Brouns F et al (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106:S5–S78. https://doi.org/10.1017/S0007114511005460
Xu X, Su S, Barnes VA et al (2013) A genome-wide methylation study on obesity. Epigenetics 8:522–533. https://doi.org/10.4161/epi.24506
Ronn T, Volkov P, Gillberg L et al (2015) Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum Mol Genet 100:9440–9445. https://doi.org/10.1093/hmg/ddv124
Higdon J, Delage B, Williams D, Dashwood R (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55:224–236. https://doi.org/10.1016/j.phrs.2007.01.009
Li Y, Tollefsbol TO (2010) Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem 17:2141–2151. https://doi.org/10.2174/092986710791299966
Zhang FF, Morabia A, Carroll J et al (2011) Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. J Nutr 141:1165–1171. https://doi.org/10.3945/jn.110.134536
Coyle YM, Xie X-J, Lewis CM et al (2007) Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue. Cancer Epidemiol Prev Biomark 16:192–196
Bryan AD, Magnan RE, Hooper AEC et al (2013) Physical activity and differential methylation of breast cancer genes assayed from saliva: a preliminary investigation. Ann Behav Med 45:89–98. https://doi.org/10.1007/s12160-012-9411-4
Zhang FF, Cardarelli R, Carroll J et al (2011) Physical activity and global genomic DNA methylation in a cancer-free population. Epigenetics 6:293–299. https://doi.org/10.4161/epi.6.3.14378
Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680
Yang H, Zhou H, Feng P et al (2010) Reduced expression of toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. J Exp Clin Cancer Res 29:92
Lau QC, Raja E, Salto-Tellez M et al (2006) RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66:6512–6520
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428
Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229
Belinsky SA, Palmisano WA, Gilliland FD et al (2002) Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res 62:2370–2377
Ortega FB, Ruiz JR, Labayen I et al (2017) The fat but fit paradox: what we know and don’t know about it. Br J Sports Med. https://doi.org/10.1136/bjsports-2016-097400
Pierce JP, Stefanick ML, Flatt SW et al (2007) Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 25:2345–2351. https://doi.org/10.1200/JCO.2006.08.6819
Satia JA, Watters JL, Galanko JA (2009) Validation of an antioxidant nutrient questionnaire in whites and African Americans. J Am Diet Assoc 109(502–508):e6
Reed K, Poulin ML, Yan L, Parissenti AM (2010) Comparison of bisulfite sequencing PCR with pyrosequencing for measuring differences in DNA methylation. Anal Biochem 397:96–106
Esteller M, Silva JM, Dominguez G et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. JNCI J Natl Cancer Inst 92:564–569
Pangeni RP, Channathodiyil P, Huen DS et al (2015) The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain. Clin Epigenetics 7:57
Toyota M, Ho C, Ahuja N et al (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59:2307–2312
Bryan A, Schmiege SJ, Broaddus MR (2007) Mediational analysis in hiv/aids research: estimating multivariate path analytic models in a structural equation modeling framework. AIDS Behav 11:365–383. https://doi.org/10.1007/s10461-006-9150-2
Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591. https://doi.org/10.1038/nrc1408
Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21:5400–5413. https://doi.org/10.1038/sj.onc.1205651
Funding
This research was funded by a grant from NIH/NCI (Grant number R01CA179963-04) to Angela Bryan.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Gillman, A.S., Gardiner, C.K., Koljack, C.E. et al. Body mass index, diet, and exercise: testing possible linkages to breast cancer risk via DNA methylation. Breast Cancer Res Treat 168, 241–248 (2018). https://doi.org/10.1007/s10549-017-4573-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-017-4573-1