Estrogen metabolism, lifetime methylation disorders, and breast cancer

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Oncogenesis can be caused by an increase in the activity of genes responsible for initiating tumor growth in stem or progenitor cells, as well as a reduction in the functioning of suppressor genes. Endogenous estrogen exposure is associated with an increased risk of breast cancer in both pre- and postmenopausal women.

The most important step in the understanding of the pathogenesis of breast cancer was the development of the theory of the switching of estrogen’s effect from hormonal to genotoxic, in which the main culprits of carcinogenesis are not chemical metabolites of estrogens, but their derivatives, corresponding to chemical procarcinogens according to their damaging characteristics. The origin of these substances and the formation of estrogen genotoxicity lies in the disruption of the inactivation process of catechol estrogens in methylation reactions.

The main epigenetic modification of the human genome is the methylation of cell DNA molecules. DNA methylation does not alter the primary sequence of nucleotides, but is necessary for the functional suppression of certain genes. The phenomenon of hypomethylation-hypermethylation underlies the long-term silencing of various genes, including tumor suppressor genes.

Nutrition and a lifestyle associated with smoking and the consumption of excessive quantities of alcohol determine estrogen metabolism and the availability of methyl groups in the body, as well as epigenetic changes in the DNA of the genome. The assessment of individual risk of breast cancer on the basis of an assay for the expression and methylation of the COMT gene responsible for estrogen metabolism seems relevant.

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About the authors

Natalia B. Chagay

Stavropol Regional Clinical Consultative and Diagnostic Center; Stavropol State Medical University

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

Russian Federation, 355032, Stavropol, str. Zapadnyy obkhod, 64; 355017, Stavropol, str. Mira, 310


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

Russian Federation, 127473,  Moscow , str, Delegatskaya, 20, b. 1

MD, PhD, Professor


  1. Сытенкова К.В., Поспехова Н.И., Поддубная И.В., Любченко Л.Н. Клинические особенности различных генотипических вариантов при наследственном и спорадическом раке молочной железы. // Российский биотерапевтический журнал. – 2011. – Т. 10. – №2. – С. 3-12. [Sytenkova KV, Pospekhova NI, Poddubnaya IV, Lyubchenko LN. Clinical features of different genotypic variants, associated with hereditary and sporadic breast cancer. Rossiiskii bioterapevticheskii zhurnal. 2011;10(2):3-12. (In Russ.)]
  2. Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer. 2013;13(7):497-510. doi:
  3. Мустафин Р.Н., Хуснутдинова Э.К. Эпигенетика канцерогенеза. // Креативная хирургия и онкология. – 2017. – Т. 7. – №3. – С. 60-67. [Mustafin RN, Khusnutdinova EK. Epigenetics of carcinogenesis. Kreativnaya khirurgiya i onkologiya. 2017;7(3):60-67. (In Russ.)]
  4. Key T, Appleby P, Barnes I, et al. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94(8):606-616. doi:
  5. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019;321(3):288-300. doi:
  6. [интернет]. Эстрадиол: метаболизм [доступ от 09.03.2018]. Доступ по ссылке [ [Internet]. Estradiol: metabolism [cited 2018 Mar 9]. Available from: (In Russ.)]
  7. Берштейн Л.М. Гормональный канцерогенез. – СПб.: Наука; 2000. [Berstein LM. Gormonal’nyy kantserogenez. Saint Petersburg: Nauka; 2000. (In Russ.)]
  8. Li F, Zhu W, Gonzalez FJ. Potential role of CYP1B1 in the development and treatment of metabolic diseases. Pharmacol Ther. 2017;178:18-30. doi:
  9. Cavalieri EL, Rogan EG. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J Steroid Biochem Mol Biol. 2011;125(3-5):169-180. doi:
  10. Cavalieri E, Rogan E. The molecular etiology and prevention of estrogen-initiated cancers: Ockham’s Razor: Pluralitas non est ponenda sine necessitate. Plurality should not be posited without necessity. Mol Aspects Med. 2014;36:1-55. doi:
  11. Dawling S, Roodi N, Parl FF. Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Cancer Res. 2003;63(12):3127-3132.
  12. Stack DE, Li G, Hill A, Hoffman N. Mechanistic insights into the Michael addition of deoxyguanosine to catechol estrogen-3,4-quinones. Chem Res Toxicol. 2008;21(7):1415-1425. doi:
  13. 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:
  14. Шахматова О.О., Комаров А.Л., Панченко Е.П. Нарушение обмена гомоцистеина как фактор риска развития сердечно-сосудистых заболеваний: влияние на прогноз и возможности медикаментозной коррекции. // Кардиология. – 2010. – Т. 50. – №1. – С. 42-50. [Shakhmatova OO, Komarov AL, Panchenko EP. Disturbances of Homocysteine Metabolism as a Risk Factor of Development of Cardiovascular Diseases: Effect on Prognosis and Possibilities of Correction With Drugs. Cardiology. 2010;50(1):42-50. (In Russ.)]
  15. Medici V, Schroeder DI, Woods R, et al. Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. Alcohol Clin Exp Res. 2014;38(6):1540-1549. doi:
  16. Чагай Н.Б., Мкртумян А.М. Метилирование эстрогенов, ожирение и рак молочной железы. // Проблемы эндокринологии. – 2018. – Т. 64. – № 4. – С. 244-251. [Chagay NB, Mkrtumyan AM. Estrogen methylation, obesity and breast cancer. Problems of endocrinology. 2018;64(4):244-251. (In Russ.)] doi:
  17. Смирнов В.В., Леонов Г.Е. Эпигенетика: теоретические аспекты и практическое значение. // Лечащий врач. – 2016. – № 12. – С. 26. [Smirnov VV, Leonov GE. Epigenetics: theoretical aspects and practical value. Practitioner. 2016;(12):26. (In Russ.)]
  18. Козлов В.А. Метилирование ДНК клетки и патология организма. // Медицинская иммунология. – 2008. – Т. 10. – № 4-5. – С. 307-318. [Kozlov VA. Methylation of cellular DNA and pathology of the organism. Medical Immunology (Russia). 2008;10(4-5):307-318. (In Russ.)] doi:
  19. [интернет]. Рак в эпигенетических исследованиях [доступ от 11.06.2019]. Доступ по ссылке: [ [Internet]. Cancer in epigenetic studies [cited 11 Jun 2019]. Available from: (In Russ.)]
  20. [интернет]. Петраш Н. Роль метилирования ДНК в канцерогенезе [доступ от 11.06.2019]. Доступ по ссылке: [ [Internet]. The role of DNA methylation in carcinogenesis [cited 2019 Jun 11.] Available from: (In Russ.)]
  21. Sproul D, Kitchen RR, Nestor CE, et al. Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol. 2012;13(10):R84. doi:
  22. Ivorra C, Fraga MF, Bayon GF, et al. DNA methylation patterns in newborns exposed to tobacco in utero. J Transl Med. 2015;13:25. doi:
  23. Vucetic Z, Kimmel J, Totoki K, et al. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010;151(10):4756-4764. doi:
  24. Bloushtain-Qimron N, Yao J, Snyder EL, et al. Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci USA. 2008;105(37):14076-14081. doi:
  25. Liu Y, Colditz GA, Rosner B, et al. Alcohol intake between menarche and first pregnancy: a prospective study of breast cancer risk. J Natl Cancer Inst. 2013;105(20):1571-1578. doi:
  26. Swift-Scanlan T, Smith CT, Bardowell SA, Boettiger CA. Comprehensive interrogation of CpG island methylation in the gene encoding COMT, a key estrogen and catecholamine regulator. BMC Med Genomics. 2014;7:5. doi:
  27. Cano A, Buque X, Martinez-Una M, et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology. 2011;54(6):1975-1986. doi:
  28. 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:
  29. Amaral CL, Bueno Rde B, Burim RV, et al. The effects of dietary supplementation of methionine on genomic stability and p53 gene promoter methylation in rats. Mutat Res. 2011;722(1):78-83. doi:
  30. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate. IARC Monogr Eval Carcinog Risks Hum. 2010;96:3-1383.
  31. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002; 87(11):1234-1245. doi:
  32. Varela-Rey M, Woodhoo A, Martinez-Chantar ML, et al. Alcohol, DNA methylation, and cancer. Alcohol Res. 2013;35(1):25-35.
  33. Allen NE, Beral V, Casabonne D, et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009;101(5):296-305. doi:
  34. Dartois L, Fagherazzi G, Baglietto L, et al. Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: Estimates from the E3N-EPIC cohort. Int J Cancer. 2016;138(10):2415-2427. doi:
  35. Masso-Welch PA, Tobias ME, Vasantha Kumar SC, et al. Folate exacerbates the effects of ethanol on peripubertal mouse mammary gland development. Alcohol. 2012;46(3):285-292. doi:
  36. Liu Y, Nguyen N, Colditz GA. Links between alcohol consumption and breast cancer: a look at the evidence. Womens Health (Lond). 2015;11(1):65-77. doi:
  37. Castro GD, Delgado de Layño AMA, Costantini MH, Castro JA. Cytosolic xanthine oxidoreductase mediated bioactivation of ethanol to acetaldehyde and free radicals in rat breast tissue. Its potential role in alcohol-promoted mammary cancer. Toxicology. 2001;160(1-3):11-18. doi:
  38. Yu HS, Oyama T, Isse T, et al. Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem Biol Interact. 2010;188(3):367-375. doi:
  39. 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:
  40. Cheng G, Li Y, Omoto Y, et al. Differential Regulation of Estrogen Receptor (ER)α and ERβ in Primate Mammary Gland. J Clin Endocrinol Metab. 2005;90(1):435-444. doi:
  41. Zhang Q, Jin J, Zhong Q, et al. ERalpha mediates alcohol-induced deregulation of Pol III genes in breast cancer cells. Carcinogenesis. 2013;34(1):28-37. doi:
  42. Rai V. The methylenetetrahydrofolate reductase C677T polymorphism and breast cancer risk in Asian populations. Asian Pac J Cancer Prev. 2014;15(14):5853-5860. doi:
  43. Zhong S, Chen Z, Yu X, et al. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer. Mol Biol Rep. 2014;41(9):5775-5785. doi:
  44. Liu W, Li Y, Li R, et al. Association of Mthfr A1298c Polymorphism with Breast Cancer and/or Ovarian Cancer Risk: An Updated Meta-Analysis. Afr J Tradit Complement Altern Med. 2016;13(5):72-86. doi:
  45. Hu J, Zhou GW, Wang N, Wang YJ. MTRR A66G polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;124(3):779-784. doi:
  46. Lu M, Wang F, Qiu J. Methionine synthase A2756G polymorphism and breast cancer risk: a meta-analysis involving 18,953 subjects. Breast Cancer Res Treat. 2010;123(1):213-217. doi:
  47. Liu M, Cui LH, Ma AG, et al. Lack of effects of dietary folate intake on risk of breast cancer: an updated meta-analysis of prospective studies. Asian Pac J Cancer Prev. 2014;15(5):2323-2328. doi:
  48. Chen P, Li C, Li X, et al. Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis. Br J Cancer. 2014;110(9):2327-2338. doi:
  49. Macacu A, Autier P, Boniol M, Boyle P. Active and passive smoking and risk of breast cancer: a meta-analysis. Breast Cancer Res Treat. 2015;154(2):213-224. doi:
  50. Gu F, Caporaso NE, Schairer C, et al. Urinary concentrations of estrogens and estrogen metabolites and smoking in caucasian women. Cancer Epidemiol Biomarkers Prev. 2013;22(1):58-68. doi:
  51. Peng J, Xu X, Mace BE, et al. Estrogen metabolism within the lung and its modulation by tobacco smoke. Carcinogenesis. 2013;34(4):909-915. doi:
  52. O’Neill B, Lauterstein D, Patel JC, et al. Striatal dopamine release regulation by the cholinergic properties of the smokeless tobacco, gutkha. ACS Chem Neurosci. 2015;6(6):832-837. doi:
  53. Wolk R, Shamsuzzaman AS, Svatikova A, et al. Hemodynamic and autonomic effects of smokeless tobacco in healthy young men. J Am Coll Cardiol. 2005;45(6):910-914. doi:
  54. Eshleman AJ, Stewart E, Evenson AK, et al. Metabolism of Catecholamines by Catechol-O-Methyltransferase in Cells Expressing Recombinant Catecholamine Transporters. J Neurochem. 1997;69(4):1459-1466. doi:
  55. Smith ML, King J, Dent L, et al. Effects of acute and sub-chronic L-dopa therapy on striatal L-dopa methylation and dopamine oxidation in an MPTP mouse model of Parkinsons disease. Life Sci. 2014;110(1):1-7. doi:
  56. Xu Q, Ma JZ, Payne TJ, Li MD. Determination of Methylated CpG Sites in the Promoter Region of Catechol-O-Methyltransferase (COMT) and their Involvement in the Etiology of Tobacco Smoking. Front Psychiatry. 2010;1:16. doi:
  57. Breton CV, Byun HM, Wenten M, et al. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;180(5):462-467. doi:
  58. White AJ, Chen J, McCullough LE, et al. Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study. Cancer Causes Control. 2015;26(12):1791-1802. doi:
  59. Tehranifar P, Wu HC, McDonald JA, et al. Maternal cigarette smoking during pregnancy and offspring DNA methylation in midlife. Epigenetics. 2018;13(2):129-134. doi:
  60. Besingi W, Johansson A. Smoke-related DNA methylation changes in the etiology of human disease. Hum Mol Genet. 2014;23(9): 2290-2297. doi:

Supplementary files

Supplementary Files Action
Fig. 1. Scheme of estrogen synthesis and metabolism with the formation of DNA adducts (adapted from Cavalieri EL, et al. [9]).

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Fig. 2. The folic acid cycle (adapted from S. Lu, et al. [13]).

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Copyright (c) 2019 Chagay N.B., Mkrtumyan A.M.

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