Methylation of estrogens, obesity and breast cancer

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Methylation of catechol estrogens is catalyzed by catechol-O-methyltransferase. Synthesis and activity of this enzyme is encoded by the COMT gene. Downregulation of COMT expression is responsible for the risk of developing estrogen-dependent tumors. Obesity is a factor determining the overall methylation status in the body.

There are two main types of adipose tissue differing in their functional and metabolic characteristics, as well as the microscopic structure: white adipose tissue (WAT) and brown adipose tissue (BAT). Lipolysis of WAT is controlled by hormone-sensitive lipase, which depends is catecholamine dependent. BAT is a special type of adipose tissue whose main function is to produce heat. Activation of β3-adrenergic receptors by catecholamines, both at the central and peripheral levels, is the primary mechanism regulating thermogenesis in mature BAT.

Obese patients develop adipose tissue hypoxia, as well as WAT and BAT dysfunction. Adrenergic stimulation of thermogenesis is unclaimed because of «whitening» of brown adipocytes, which manifests itself as degradation of mitochondria. Redirection of stimulation of hormone-sensitive lipase by catecholamines to WAT and the increased need to enhance COMT expression are the potential consequences of modifying the BAT metabolism.

Estrogens are natural modulators of lipolysis (as they selectively affect activity of hormone-sensitive lipase) and regulators of BAT thermogenesis. Obesity is accompanied by elevated synthesis of estrone. However, in postmenopausal women it is characterized by a decrease in the total mass and activity of BAT. The role of BAT in the progression or inhibition of growth of the estrogen-dependent tumor tissue at premenopausal and postmenopausal age has not been studied yet and is of interest to researchers. The possible correlation between the activity of brown adipocytes and the COMT expression level is discussed in the context of the risk of developing benign breast dysplasia and cancer.

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About the authors

Natalia B. Chagay

Stavropol Regional Clinical Consultative and Diagnostic Center

Author for correspondence.
ORCID iD: 0000-0001-8022-9291
SPIN-code: 2323-7791


Russian Federation, 64, Zapadnyy obkhod, Stavropol, 355029

Ashot M. Mkrtumyan

Moscow State University of Medicine and Dentistry named after A.I. Evdokimov

ORCID iD: 0000-0003-1316-5245
SPIN-code: 1980-8700

MD, PhD, Professor

Russian Federation, 20/1, Delegatskaya street, Moscow, 127473


  1. Берштейн Л.М. Гормональный канцерогенез. — СПб.: Наука; 2000. [Berstein LM. Hormonal carcinogenesis. Saint-Petersburg: Nauka; 2000. (In Russ.)].
  2. Берштейн Л.М. Онкоэндокринология. Традиции, современность, перспективы. — СПб.: Наука; 2004. [Berstein LM. Onkoendokrinologiya. Traditsii, sovremennost’, perspektivy. Saint-Petersburg: Nauka; 2004. (In Russ.)].
  3. Medbiol ru [Интернет]. Эстрадиол: метаболизм. Доступ от 09.03.18. Доступ по ссылке [ [internet]. Estradiol: metabolism [cited 2018 mar 9]. (In RFuss.)]. Available from:
  4. Samuni AM, Chuang EY, Krishna MC, et al. Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: chemoprevention strategies with antioxidants. Proc Natl Acad Sci USA. 2003;100(9):5390-5395.doi: 10.1073/pnas.0930078100
  5. Zahid M, Saeed M, Lu F, et al. Inhibition of Catechol-O-Methyltransferase increases estrogen-DNA adduct formation. Free Radic Biol Med. 2007;43(11):1534-1540.doi: 10.1016/j.freeradbiomed.2007.08.005
  6. Monteiro JP, Wise C, Morine MJ, et al. Methylation potential associated with diet, genotype, protein, and metabolite levels in the delta obesity vitamin study. Genes Nutr. 2014;9(3):403.doi: 10.1007/s12263-014-0403-9
  7. Wen W, Ren Z, Shu Xo, et al. Expression of cytochrome P450 1b1 and catechol-O-methyltransferase in breast tissue and their associations with breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2007;16(5):917-920. doi: 10.1158/1055-9965.epi-06-1032
  8. Wan GX, Cao YW, Li WQ, et al. The Catechol-O-Methyltransferase Val158met polymorphism contributes to the risk of breast cancer in the Chinese population: an updated metaanalysis. J Breast Cancer. 2014;17(2):149-156. doi: 10.4048/jbc.2014.17.2.149
  9. Tian C, Liu L, Yang X, et al. The Val158met polymorphism in the COMT gene is associated with increased cancer risks in Chinese population. Tumour Biol. 2014;35(4):3003-3008.doi: 10.1007/s13277-013-1387-6
  10. Yager JD. Catechol-O-Methyltransferase: characteristics, polymorphisms and role in breast cancer. Drug Discov Today Dis Mech. 2012;9(1-2):E41-E46. doi: 10.1016/j.ddmec.2012.10.002
  11. Li K, Li W, Zou H. Catechol-O-Methyltransferase Val158met polymorphism and breast cancer risk in Asian population. Tumour Biol. 2014;35(3):2343-2350. doi: 10.1007/s13277-013-1310-1
  12. Qin X, Peng Q, Qin A, et al. Association of COMT Val158met polymorphism and breast cancer risk: an updated metaanalysis. Diagn Pathol. 2012;7:136. doi: 10.1186/1746-1596-7-136
  13. Ding H, Fu Y, Chen W, Wang Z. COMT Val158met polymorphism and breast cancer risk: evidence from 26 case control studies. Breast Cancer Res Treat. 2010;123(1):265-270.doi: 10.1007/s10549-010-0759-5
  14. He XF, Wei W, Li SX, et al. Association between the COMT Val158met polymorphism and breast cancer risk: a metaanalysis of 30,199 cases and 38,922 controls. Mol Biol Rep. 2012;39(6):6811-6823. doi: 10.1007/s11033-012-1506-2
  15. Fischer LM, Da Costa KA, Kwock L, et al. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 2010;92(5):1113-1119. doi: 10.3945/ajcn.2010.30064
  16. Crooke PS, Justenhoven C, Brauch H, et al. Estrogen metabolism and exposure in a genotypic-phenotypic model for breast cancer risk prediction. Cancer Epidemiol Biomarkers Prev. 2011;20(7):1502-1515. doi: 10.1158/1055-9965.epi-11-0060
  17. Dominguez-Salas P, Moore SE, Cole D, et al. DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr. 2013;97(6):1217-1227. doi: 10.3945/ajcn.112.048462
  18. Shukla SD, Velazquez J, French SW, et al. Emerging role of epigenetics in the actions of alcohol. Alcohol Clin Exp Res. 2008; 32(9):1525-1534. doi: 10.1111/j.1530-0277.2008.00729.x
  19. Purohit V, Abdelmalek MF, Barve S, et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr. 2007;86(1):14-24.doi: 10.1093/ajcn/86.1.14
  20. Elshorbagy AK, Nijpels G, Valdivia-Garcia M, et al. S-adenosylmethionine is associated with fat mass and truncal adiposity in older adults. J Nutr. 2013;143(12):1982-1988.doi: 10.3945/jn.113.179192
  21. Habib CN, Al-Abd AM, Tolba MF, et al. Leptin influences estrogen metabolism and accelerates prostate cell proliferation. Life Sci. 2015;121:10-15. doi: 10.1016/J.Lfs.2014.11.007
  22. Манухин И.Б., Геворкян М.А., Чагай Н.Б. Ановуляция и инсулинорезистентность. — М.: ГЭОТАР-МЕДИА; 2006. [Manukhin IB, Gevorkyan MA, Chagay NB. Anovulyatsiya i Insulinorezistentnost’. Мoscow: GEOTAR-MEDIA; 2006. (In Russ.)].
  23. Чагай Н.Б. Метаболические нарушения и их коррекция при синдроме хронической ановуляции: Дис. … д-ра мед. наук. — М. 2012. [Chagay NB. Metabolicheskie narusheniya i ikh korrektsiya pri sindrome khronicheskoy anovulyatsii. [Dissertation]. Moscow; 2012. (In Russ.)].
  24. Boonyaratanakornkit V, Pateetin P. The role of ovarian sex steroids in metabolic homeostasis, obesity, and postmenopausal breast cancer: molecular mechanisms and therapeutic implications. Biomed Res Int. 2015;2015:140196. doi: 10.1155/2015/140196
  25. Hovey RC, Aimo L. Diverse and active roles for adipocytes during mammary gland growth and function. J Mammary Gland Biol Neoplasia. 2010;15(3):279-290. doi: 10.1007/S10911-010-9187-8
  26. Hauner D, Hauner H. Metabolic syndrome and breast cancer: is there a link? Breast Care (Basel). 2014;9(4):277-281.doi: 10.1159/000365951
  27. Cheraghi Z, Poorolajal J, Hashem T, et al. Effect of body mass index on breast cancer during premenopausal and postmenopausal periods: a metaanalysis. Plos One. 2012;7(12):E51446.doi: 10.1371/journal.pone.0051446
  28. Xia X, Chen W, Li J, et al. Body mass index and risk of breast cancer: a nonlinear dose-response metaanalysis of prospective studies. Sci Rep. 2014;4:7480. doi: 10.1038/srep07480
  29. Keum N, Greenwood DC, Lee DH, et al. Adult weight gain and adiposity-related cancers: a dose-response metaanalysis of prospective observational studies. J Natl Cancer Inst. 2015;107(2).doi: 10.1093/jnci/Djv088
  30. Кокшарова Е.О., Майоров А.Ю., Шестакова М.В., Дедов И.И. Метаболические особенности и терапевтический потенциал бурой и «бежевой» жировой ткани. // Сахарный диабет. — 2014. — Т. 17. — № 4. — С. 5—15. [Koksharova EO, Mayorov AYu, Shestakova MV, Dedov II. Metabolic characteristics and the therapeutic potential of brown and «beige» adipose tissue. Diabetes Mellitus. 2014;17(4):5-15. (In Russ.)].doi: 10.14341/dm201445-15
  31. Мяделец О.Д., Мяделец В.О., Соболевская И.С., Кичигина Т.Н. Белая и бурая жировые ткани: взаимодействие со скелетной мышечной тканью. // Вестник ВГМУ. — 2014. — Т. 13. — № 5. — С. 32—44. [Myadelets ОD, Myadelets VO, Sobolevskaya IS, Kichigina TN. Belaya i buraya zhirovye tkani: vzaimodeystvie so skeletnoy myshechnoy tkan’yu. Vestnik VGMU. 2014;13(5):32-44. (In Russ.)].
  32. Labbé SM, Caron A, Lanfray D, et al. Hypothalamic control of brown adipose tissue thermogenesis. Frontiers in Systems Neuroscience. 2015;9. doi: 10.3389/fnsys.2015.00150
  33. Almind K, Manieri M, Sivitz WI, et al. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci USA. 2007;104(7):2366-2371. doi: 10.1073/pnas.0610416104
  34. Schulz TJ, Tseng YH. Brown adipose tissue: development, metabolism and beyond. Biochem J. 2013;453(2):167-178.doi: 10.1042/bj20130457
  35. Townsend K, Tseng YH. Brown adipose tissue: recent insights into development, metabolic function and therapeutic potential. Adipocyte. 2012;1(1):13-24. doi: 10.4161/adip.18951
  36. Shimizu I, Aprahamian T, Kikuchi R, et al. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest. 2014;124(5):2099-2112. doi: 10.1172/jci71643
  37. Poher AL, Altirriba J, Veyrat-Durebex C, Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Front Physiol. 2015;6:4.doi: 10.3389/aphys.2015.00004
  38. Шварц В. Воспаление жировой ткани. Часть 1. Морфологические и функциональные проявления. // Проблемы Эндокринологии. — 2009. — Т. 55. — № 4. — С. 44—49. [Shvarts V. Adipose tissue inflammation. Part 1. Morphological and functional manifestations. Problems of Endocrinology. 2009;55(4):44-49. (In Russ.)]. doi: 10.14341/probl200955444-49
  39. Романцова Т.И. Эпидемия ожирения: очевидные и вероятные причины. // Ожирение и метаболизм. — 2011. — Т. 8. — № 1. — C. 5—19. [Romantsova TI. Epidemiya ozhireniya: ochevidnye i veroyatnye prichiny. Obesity and Metabolism. 2011;8(1):5-19. (In Russ.)]. doi: 10.14341/2071-8713-5186
  40. Subramanian V, Ferrante AWJr. Obesity, inflammation, and macrophages. Nestle Nutr Workshop Ser Pediatr Program. 2009;63:151-159; Discussion 159-162, 259-168. doi: 10.1159/000209979
  41. Шварц В. Воспаление жировой ткани: враг или друг? // Цитокины и воспаление. — 2013. — Т. 12. — № 1—2. — С. 13—21. [Shvarts V. Inflammation of adipose tissue: foe or friend? Cytokines & Inflammation. 2013;12(1-2):13-21. (In Russ.)].
  42. Никитина В.В., Захарова Н.Б. Значение МСР-1 как предиктора сосудистых нарушений. // Саратовский научно-медицинский журнал. — 2010. — Т. 6. — № 4. — C. 786—790. [Nikitina VV, Zakharova NB. Value МCP-1 as predict vascular disturbances. Saratov Journal of Medical Scientific Research. 2010;6(4):786-790. (In Russ.)].
  43. Margolis M, Perez OJr, Martinez M, et al. Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: results of a pilot study. Biochimie. 2015;108:133-139. doi: 10.1016/j.biochi.2014.11.009
  44. Garcia-Martin R, Alexaki Vi, Qin N, et al. Adipocyte-specific hypoxia-inducible factor 2alpha deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation. Mol Cell Biol. 2015;36(3):376-393.doi: 10.1128/mcb.00430-15
  45. Ngo DT, Farb MG, Kikuchi R, et al. Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial frowth factor-α, in human obesity. Circulation. 2014;130(13):1072-1080.doi: 10.1161/circulationaha.113.008171
  46. Trayhurn P, Alomar SY. Oxygen deprivation and the cellular response to hypoxia in adipocytes — perspectives on white and brown adipose tissues in obesity. Front Endocrinol (Lausanne). 2015;6:19.doi: 10.3389/fendo.2015.00019
  47. Lee KY, Gesta S, Boucher J, et al. The differential role of HIFLbeta/ARNT and the hypoxic response in adipose function, fibrosis, and inflammation. Cell Metab. 2011;14(4):491-503.doi: 10.1016/j.cmet.2011.08.006
  48. Martinez de Morentin PB, Gonzalez-Garcia I, Martins L, et al. Estradiol regulates brown adipose tissue thermogenesis VIA hypothalamic AMPK. Cell Metab. 2014;20(1):41-53.doi: 10.1016/j.cmet.2014.03.031
  49. Nadal-Casellas A, Proenza AM, Llado I, Gianotti M. Effects of ovariectomy and 17-beta estradiol replacement on rat brown adipose tissue mitochondrial function. Steroids. 2011;76(10-11):1051-1056. doi: 10.1016/j.steroids.2011.04.009
  50. Cao Q, Hersl J, La H, et al. A pilot study of FDG Pet/Ct detects a link between brown adipose tissue and breast cancer. BMC Cancer. 2014;14:126. doi: 10.1186/1471-2407-14-126
  51. Gadea E, Thivat E, Merlin C, et al. Brown adipose tissue activity in relation to weight gain during chemotherapy in breast cancer patients: a pilot study. Nutr Cancer. 2014;66(7):1092-1096.doi: 10.1080/01635581.2014.948212
  52. Master SR, Hartman JL, D’cruz CM , et al. Functional microarray analysis of mammary organogenesis reveals a developmental role in adaptive thermogenesis. Mol Endocrinol. 2002;16(6):1185-1203.doi: 10.1210/mend.16.6.0865
  53. Sanchez-Alvarez R, Martinez-Outschoorn UE, Lamb R, et al. Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin. Cell Cycle. 2013;12(1):172-182. doi: 10.4161/cc.23058
  54. Jones PL, Buelto D, Tago E. Abnormal mammary adipose tissue environment of BRCA1 mutant mice show a persistent deposition of highly vascularized multilocular adipocytes. J Cancer Sci Ther. 2011;01(S2). doi: 10.4172/1948-5956.s2-004
  55. Wang F, Gao S, Chen F, et al. Mammary fat of breast cancer: gene expression profiling and functional characterization. Plos One. 2014;9(10):E109742. doi: 10.1371/journal.pone.0109742
  56. Chen Y, Cairns R, Papandreou I, et al. Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. Plos One. 2009;4(9):E7033. doi: 10.1371/journal.pone.0007033
  57. Hartung JE, Ciszek BP, Nackley AG. Beta2- and beta3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines. Pain. 2014;155(7):1346-1355.doi: 10.1016/j.pain.2014.04.011
  58. Tchivileva IE, Tan KS, Gambarian M, et al. Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol Immunol. 2009;46(11-12):2256-2266.doi: 10.1016/j.molimm.2009.04.008

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Abstract: 24


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