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Body mass index associated with genome-wide methylation in breast tissue

  • Epidemiology
  • Published:
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Abstract

Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value <0.05. Gene expression microarray data was used to identify which of the BMI-associated methylation sites also showed correlation with gene expression. Gene set enrichment analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value <0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes.

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References

  1. Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  2. Sommer S, Fuqua SA (2001) Estrogen receptor and breast cancer. Semin Cancer Biol 11(5):339–352. doi:10.1006/scbi.2001.0389

    Article  CAS  PubMed  Google Scholar 

  3. Millikan RC, Newman B, Tse CK et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109(1):123–139. doi:10.1007/s10549-007-9632-6

    Article  PubMed Central  PubMed  Google Scholar 

  4. Carey LA, Perou CM, Livasy CA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  CAS  PubMed  Google Scholar 

  5. Carmichael AR (2006) Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 113(10):1160–1166. doi:10.1111/j.1471-0528.2006.01021.x

    Article  CAS  PubMed  Google Scholar 

  6. Carmichael AR, Bates T (2004) Obesity and breast cancer: a review of the literature. Breast 13(2):85–92. doi:10.1016/j.breast.2003.03.001

    Article  CAS  PubMed  Google Scholar 

  7. Gaudet MM, Press MF, Haile RW et al (2011) Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger. Breast Cancer Res Treat 130(2):587–597. doi:10.1007/s10549-011-1616-x

    Article  PubMed Central  PubMed  Google Scholar 

  8. Phipps AI, Buist DS, Malone KE et al (2012) Breast density, body mass index, and risk of tumor marker-defined subtypes of breast cancer. Ann Epidemiol. doi:10.1016/j.annepidem.2012.02.002

    PubMed Central  PubMed  Google Scholar 

  9. Ritte R, Lukanova A, Berrino F et al (2012) Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res 14(3):R76. doi:10.1186/bcr3186

    Article  PubMed Central  PubMed  Google Scholar 

  10. Yang XR, Chang-Claude J, Goode EL et al (2011) Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 103(3):250–263. doi:10.1093/jnci/djq526

    Article  PubMed Central  PubMed  Google Scholar 

  11. Enger SM, Ross RK, Paganini-Hill A et al (2000) Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies. Cancer Epidemiol Biomark Prev 9(7):681–687

    CAS  Google Scholar 

  12. Suga K, Imai K, Eguchi H et al (2001) Molecular significance of excess body weight in postmenopausal breast cancer patients, in relation to expression of insulin-like growth factor I receptor and insulin-like growth factor II genes. Jpn J Cancer Res 92(2):127–134

    Article  CAS  PubMed  Google Scholar 

  13. Sun X, Casbas-Hernandez P, Bigelow C et al (2012) Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat 131(3):1003–1012. doi:10.1007/s10549-011-1789-3

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13(2):279–292. doi:10.1677/erc.1.00729

    Article  CAS  PubMed  Google Scholar 

  15. Parrizas M, Saltiel AR, LeRoith D (1997) Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways. J Biol Chem 272(1):154–161

    Article  CAS  PubMed  Google Scholar 

  16. Mantovani A, Allavena P, Sica A et al (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205

    Article  CAS  PubMed  Google Scholar 

  17. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867. doi:10.1038/nature01322

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293(5532):1068–1070. doi:10.1126/science.1063852

    Article  CAS  PubMed  Google Scholar 

  19. Sandoval J, Heyn H, Moran S et al (2011) Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6(6):692–702

    Article  CAS  PubMed  Google Scholar 

  20. Irizarry RA, Hobbs B, Collin F et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264. doi:10.1093/biostatistics/4.2.249

    Article  PubMed  Google Scholar 

  21. Handle Illumina methylation data. R package

  22. 1000 Genomes Project Consortium, Abecasis GR, Auton A et al (2012) An integrated map of genetic variation from 1092 human genomes. Nature 491(7422):56–65. doi:10.1038/nature11632

    Article  Google Scholar 

  23. Price ME, Cotton AM, Lam LL et al. (2013) Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenetics Chromatin. 6(1):4,8935-6-4. doi: 10.1186/1756-8935-6-4

  24. Xu Z, Taylor JA (2014) Genome-wide age-related DNA methylation changes in blood and other tissues relate to histone modification, expression and cancer. Carcinogenesis 35(2):356–364. doi:10.1093/carcin/bgt391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100(16):9440–9445. doi:10.1073/pnas.1530509100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. NCBI News, September (2009) Bethesda (MD), National Center for Biotechnology Information (US), 2009

  27. Wu MC, Lin X (2009) Prior biological knowledge-based approaches for the analysis of genome-wide expression profiles using gene sets and pathways. Stat Methods Med Res 18(6):577–593. doi:10.1177/0962280209351925

    Article  PubMed Central  PubMed  Google Scholar 

  28. Creighton CJ, Sada YH, Zhang Y et al (2011) A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat. doi:10.1007/s10549-011-1595-y

    PubMed Central  Google Scholar 

  29. Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103(5):1412–1417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Price ME, Cotton AM, Lam LL, et al (2013) Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenet Chromatin 6(1):4,8935-6-4. doi: 10.1186/1756-8935-6-4

  31. Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186. doi:10.1038/ng.298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20(24):3139–3155. doi:10.1038/sj.onc.1204341

    Article  CAS  PubMed  Google Scholar 

  33. Fantuzzi G (2005) Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115(5):911–920. doi:10.1016/j.jaci.2005.02.023

    Article  CAS  PubMed  Google Scholar 

  34. Antuna-Puente B, Feve B, Fellahi S et al (2008) Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab 34(1):2–11. doi:10.1016/j.diabet.2007.09.004

    Article  CAS  PubMed  Google Scholar 

  35. Knupfer H, Preiss R (2007) Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 102(2):129–135. doi:10.1007/s10549-006-9328-3

    Article  PubMed  Google Scholar 

  36. Mantovani A, Marchesi F, Porta C et al (2007) Inflammation and cancer: breast cancer as a prototype. Breast 16(Suppl 2):S27–S33. doi:10.1016/j.breast.2007.07.013

    Article  PubMed  Google Scholar 

  37. Sundaram S, Freemerman AJ, Johnson AR et al (2013) Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer. Breast Cancer Res Treat 142(3):489–503. doi:10.1007/s10549-013-2741-5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Singh A, Purohit A, Ghilchik MW et al (1999) The regulation of aromatase activity in breast fibroblasts: the role of interleukin-6 and prostaglandin E2. Endocr Relat Cancer 6(2):139–147

    Article  CAS  PubMed  Google Scholar 

  39. Zhao Y, Nichols JE, Valdez R et al (1996) Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol Endocrinol 10(11):1350–1357

    CAS  PubMed  Google Scholar 

  40. Kitawaki J, Kusuki I, Koshiba H et al (1999) Leptin directly stimulates aromatase activity in human luteinized granulosa cells. Mol Hum Reprod 5(8):708–713

    Article  CAS  PubMed  Google Scholar 

  41. Magoffin DA, Weitsman SR, Aagarwal SK et al (1999) Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women. Ginekol Pol 70(1):1–7

    CAS  PubMed  Google Scholar 

  42. Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17(8):328–336. doi:10.1016/j.tem.2006.08.006

    Article  CAS  PubMed  Google Scholar 

  43. Casbas-Hernandez P, D’Arcy M, Roman-Perez E et al (2013) Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Breast Cancer Res 15(5):R82

    Article  PubMed Central  PubMed  Google Scholar 

  44. Di LJ, Byun JS, Wong MM et al (2013) Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4:1449. doi:10.1038/ncomms2438

    Article  PubMed Central  PubMed  Google Scholar 

  45. Byun JS, Gardner K (2013) C-terminal binding protein: a molecular link between metabolic imbalance and epigenetic regulation in breast cancer. Int J Cell Biol 2013:647975. doi:10.1155/2013/647975

    Article  PubMed Central  PubMed  Google Scholar 

  46. Tao MH, Marian C, Nie J et al (2011) Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study. Am J Clin Nutr 94(3):831–838. doi:10.3945/ajcn.110.009365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Dumitrescu RG, Marian C, Krishnan SS et al (2010) Familial and racial determinants of tumour suppressor genes promoter hypermethylation in breast tissues from healthy women. J Cell Mol Med 14(6B):1468–1475. doi:10.1111/j.1582-4934.2009.00924.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Choi JD, Lee JS (2013) Interplay between epigenetics and genetics in cancer. Genomics Inform 11(4):164–173. doi:10.5808/GI.2013.11.4.164

    Article  PubMed Central  PubMed  Google Scholar 

  49. Trujillo KA, Heaphy CM, Mai M et al (2011) Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 129(6):1310–1321. doi:10.1002/ijc.25788

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Heaphy CM, Bisoffi M, Fordyce CA et al (2006) Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 119(1):108–116. doi:10.1002/ijc.21815

    Article  CAS  PubMed  Google Scholar 

  51. Heaphy CM, Griffith JK, Bisoffi M (2009) Mammary field cancerization: molecular evidence and clinical importance. Breast Cancer Res Treat 118(2):229–239. doi:10.1007/s10549-009-0504-0

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to acknowledge Monica D’Arcy, Xuezheng Sun, and Thomas G. Stewart for statistical support.

Conflict of interests

The authors declare that they have no conflict of interests.

Ethical standards

The experiments performed for this research comply with the current laws of the country in which they were performed.

Funding

This research was funded, in part, by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (NIH/NCI P50-CA58223), the National Cancer Institute/National Institute of Environmental Health Sciences Breast Cancer and the Environment Research Program (U01 – ES019472), and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA-ES049032-18, ZIA-ES049033-18). WRR was supported by the National Cancer Institute (K01-CA172717-01).

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Authors and Affiliations

  1. Department of Epidemiology, University of North Carolina at Chapel Hill, CB #7435, 2101 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA

    Brionna Y. Hair, Erin L. Kirk, Whitney R. Robinson, Andrew F. Olshan, Kathleen Conway & Melissa A. Troester

  2. Epidemiology Branch, and Epigenomics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences (NIH), Research Triangle Park, NC, USA

    Zongli Xu, Sophia Harlid & Jack A. Taylor

  3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Rupninder Sandhu, Whitney R. Robinson & Kathleen Conway

  4. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Michael C. Wu

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  1. Brionna Y. Hair
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  2. Zongli Xu
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Correspondence to Brionna Y. Hair.

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Hair, B.Y., Xu, Z., Kirk, E.L. et al. Body mass index associated with genome-wide methylation in breast tissue. Breast Cancer Res Treat 151, 453–463 (2015). https://doi.org/10.1007/s10549-015-3401-8

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