Estrogen metabolism, lifetime methylation disorders, and breast cancer

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Abstract


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.


Natalia B. Chagay

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

Author for correspondence.
Email: chagaynb@gmail.com
ORCID iD: 0000-0001-8022-9291
SPIN-code: 2323-7791

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

MD, PhD

Ashot M. Mkrtumyan

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

Email: vagrashot@mail.ru
ORCID iD: 0000-0003-1316-5245
SPIN-code: 1980-8700

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

MD, PhD, Professor

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Supplementary files

Supplementary Files Action
1. Fig. 1. Scheme of estrogen synthesis and metabolism with the formation of DNA adducts (adapted from Cavalieri EL, et al. [9]). View (273KB) Indexing metadata
2. Fig. 2. The folic acid cycle (adapted from S. Lu, et al. [13]). View (263KB) Indexing metadata

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