Molecular mechanism of mammographic density formation of the breast tissue
Summary. Mammographic tissue density (MTD) is the extent to which radiodense fibroglandular tissue is spread in the mammary gland (MG). The mammogram demonstrates presence of two constituent components in the breast — fibroglandular and adipose tissues, which have different X-ray attenuation coefficients. The density of breast tissue can be a risk factor for breast cancer. Purpose of the study. Тo identify changes in the redox state of breast tissue in pre- and postmenopausal patients, in whom mammographic tissue density and obesity are also recorded. Materials and methods. The studies were carried out on biopsy material from 46 pre- (group 1) and postmenopausal (group 2) obese patients. Mammograms were scanned, the area of the dense sites was calculated in the ArchiCAD Graphisoft 14 program and classified according to the B1-RADS system according to the percentage of mammographic density (MD). Research results. It was revealed that the average percentage of MTD in the MG decreased with age — both in women who developed breast cancer (BC) and those who did not get sick — but at any age, the percentage of dense tissue in the breast was higher in women who developed breast cancer. Body mass index was positively associated with the risk of breast cancer in postmenopausal women and negatively in premenopausal women. According to the results of our studies and studies of other authors, in patients with a breast density of 75%, the risk of breast cancer is 4–6 times higher than in women with low or no MD of MG. In both premenopausal and postmenopausal women, the level of superoxide radicals generation in the MG with MD significantly increases compared to controls. Body mass index is inversely correlated with the percentage of mammographic density, since more weight is associated with a larger area of loose mammogram tissue, which reflects more AT in the MG. In patients with MD MG in pre- and postmenopausal age, the levels of 8-oxodG in the urine are higher than the control values and are determined in the range of 1.89–2.15 nmol/kg body weight and 2.58-3.0 nmol / kg body weight respectively. In addition, the levels of 8-oxodG in postmenopausal patients were higher than in those who were premenopausal. A significant association of high levels of matrix metalloproteinase-2 activity with high MD was revealed. In the group of patients, whose MD was 38 ± 7.7%, the levels of matrix metalloproteinase-2 activity in the MG tissue were 1.9 times higher than those in the group of patients whose MD was 20 ± 18.3%. Conclusions. Our results suggest that endogenous processes that lead to DNA damage and increased cell proliferation can contribute to the formation of MDT in the MG. These include all redox-dependent processes that occur in mitochondria and immune cells, which during their functioning could cause: superoxide radicals generation; increase of the activity of cells with NO-synthase activity; formation of lipid and protein peroxidation products; turninig on redox-dependent processes of AT degradation (activation of matrix metalloproteinase); increase of the metabolism of hormones by cytochrome P-450, for example, CYP 1A2, which metabolizes estradiol to 2-hydroxy and 4-hydroxy metabolites, the second of which is estrogenic and carcinogenic. Catechol estrogens can promote carcinogenesis by becoming a source of reactive oxygen species and entering the redox cycle (that is, repeated cycles of oxidation and reduction with the formation of 3, 4-semiquinones and 3, 4-quinones, which are highly reactive, can bind with DNA and create depurinating adducts that induce gene mutations and can lead to fibrous remodeling of adipose tissue and initiation of proliferation.
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