YU.V. GARIFULLOVA, L.I. MALTSEVA

 Kazan State Medical Academy — Branch Campus of the FSBEI FPE RMACPE MOH Russia, Kazan, Russia

Contact details:

Garifullova Yu.V. — PhD. (Medicine), Associate Professor of the Department of Obstetrics and Gynecology

Address: 36 Butlerov St., 420012 Kazan, Russian Federation, tel.: +7-919-637-22-33, e-mail: gamil.garifullov@yandex.ru

The article presents current data on the formation of benign breast dysplasia (BPH) during menopausal transition and postmenopause. The main links in the pathogenesis of breast cancer in postmenopausal women are considered, with an emphasis on the role of immune inflammation, aging, and impaired glandular involution. The research showed the importance of epigenetic disorders, their association with insulin resistance, and high mammographic density of mammary glands as the most significant risk factor for breast cancer. The clinical features and pathogenesis of benign dysplasia in menopausal women determine approaches to the prevention of breast neoplasia.

Key words: benign breast diseases, meno- and postmenopause, inflammation, insulin resistance, epigenetic disorders.

REFERENCES

1. Giacomini D., Páez-Pereda M., Stalla J. et al. Molecular Interaction of BMP-4, TGF-β, and Estrogens in Lactotrophs: Impact on the PRL Promoter. Mol. Endocrinol, 2009, vol. 23 (7), pp. 1102–1114. DOI: 10.1210/me.2008-0425
2. Jasleen Kaur, Kamal Bhusal. Hyperprolactinemia. StatPearls, avaialble at: https://www.ncbi.nlm.nih.gov/books/NBK537331
3. Wolfson B., Eades G., Zhou Q. Adipocyte activation of cancer stem cell signaling in breast cancer. Biol. Chem, 2015, vol. 6 (2), pp. 39–47. DOI: 10.4331/wjbc.v6.i2.39
4. Gyamfi J., Eom M., Koo J.S., Choi J. Multifaceted Roles of Interleukin-6 in Adipocyte-Breast Cancer Cell Interaction. Transl. Oncol, 2018, vol. 11 (2), pp. 275–285. DOI: 10.1016/j.tranon.2017.12.009
5. Zhang G., Hou S., Li S. et al. Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review). Int. J. Oncol, 2024, vol. 64 (5), p. 48. DOI: 10.3892/ijo.2024.5636
6. Wiley C.D., Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat. Metab, 2021, vol. 3 (10), pp. 1290–1301.
7. Ou H., Hoffmann R., González-López C. et al. Cellular senescence in cancer: from mechanisms to detection. Mol. Oncol, 2021, vol. 15 (10), pp. 2634–2671.
8. Oey O. et al. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. Clin. Oncol, 2023, vol. 14 (7), pp. 230–246.
9. DeSantis C., Ma J., Bryan L., Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin, 2014, vol. 64 (1), pp. 52–62. DOI: 10.3322/caac.21203
10. Lacina L., Kolář M., Pfeiferová L. et al. Wound healing: insights into autoimmunity, ageing, and cancer ecosystems through inflammation and IL-6 modulation. Front Immunol, 2024, vol. 15. 1403570. DOI: 10.3389/fimmu.2024.1403570
11. Indra Heckenbach, Rita Peila, Christopher Benz et.al. Cellular senescence predicts breast cancer risk from benign breast disease biopsy images. Breast Cancer Research, 2025, vol. 27, article 37.
12. Abubakar M., Fan S., Klein A. et al. Spatially Resolved Single-Cell Morphometry of Benign Breast Disease Biopsy Images Uncovers Quantitative Cytomorphometric Features Predictive of Subsequent Invasive Breast Cancer Risk. Mod Pathol, 2025, vol. 38 (7), p. 100767. DOI: 10.1016/j.modpat.2025.100767
13. Zhang S., Meng Y., Zhou L. et al. Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy. J. Med. Comm, 2022, vol. 3 (4), p. e173. DOI: 10.1002/mco2.173
14. Grivennikov S.I., Greten F.R., Karin M. Immunity, inflammation, and cancer. Cell, 2010, vol. 140 (6), pp. 883–899.
15. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer‐related inflammation. Nature, 2008, vol. 454 (7203), pp. 436–444.
16. Orsatti C.L., Orsatti F.L., De Souza J.P.E.A. et al. Postmenopausal women treated for breast cancer with insulin resistance: clinical, analytical, cross-sectional. Women Health, 2024, vol. 64 (7), pp. 584–594. DOI: 10.1080/03630242.2024.2383289
17. Gonullu G., Ersoy C., Ersoy A. et al. Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early-stage breast cancer. Cytokine, 2005, vol. 31 (4), pp. 264–269. DOI: 10.1016/j.cyto.2005.05.003
18. Chiefari E., Mirabelli M., La Vignera S. et al. Insulin Resistance and Cancer: In Search for a Causal Link. Int. J. Mol. Sci, 2021, vol. 22 (20), p. 11137. DOI: 10.3390/ijms222011137
19. Klimczak S., Śliwińska A. Epigenetic regulation of inflammation in insulin resistance. Semin Cell Dev. Biol, 2024, vol. 154 (Pt C), pp. 185–192. DOI: 10.1016/j.semcdb.2022.09.004
20. Deng J., Liao Y., Liu J. et al. Research progress on epigenetics of diabetic cardiomyopathy in type 2 diabetes. Front. Cell. Dev. Biol, 2021, vol. 9. 777258.
21. Filardi T., Catanzaro G., Mardente S. et al. Non-coding RNA: role in gestational diabetes pathophysiology and complications. Int. J. Mol. Sci, 2020, vol. 21, p. 4020.
22. Wu D., Hu D., Chen H. et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature, 2018, vol. 559, pp. 637–641.
23. Kresovich J.K., Xu Z., O’Brien K.M. et al. Methylation-Based Biological Age and Breast Cancer Risk. J. Natl. Cancer Inst, 2019, vol. 111 (10), pp. 1051–1058.
24. Xu Z., Sandler D.P., Taylor J.A. Blood DNA Methylation and Brest Cancer: A Prospective Case-Cohort Analisis in the Sister Study. J. Natl. Cancer Inst, 2020, vol. 112 (1), pp. 87–94.
25. Pereira-Santos M., Costa P.R., Assis A.M. et al. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes. Rev, 2015, vol. 16 (4), pp. 341–349. DOI: 10.1111/obr.12239
26. Bennour I., Haroun N., Sicard F. et al. Vitamin D and Obesity/Adiposity-A Brief Overview of Recent Studies. Nutrients, 2022, vol. 14 (10), p. 2049. DOI: 10.3390/nu14102049
27. Pramono A., Jocken J.W.E., Blaak E.E. Vitamin D deficiency in the aetiology of obesity-related insulin resistance. Diabetes Metab. Res. Rev, 2019, vol. 35 (5), p. e3146. DOI: 10.1002/dmrr.3146
28. Fisher U., Baum F. Mammografiya:100 klinicheskikh sluchayev [Mammography: 100 clinical cases]. Moscow: MEDpress-inform, 2009. 368 p.
29. Bodewes F.T.H., van Asselt A.A., Dorrius M.D. et al. Mammographic breast density and the risk of breast cancer: A systematic review and meta-analysis. The Breast, 2022, vol. 66, pp. 62–68.
30. Ibrahim H. Kanbaiti. Dense Breast Tissue in Postmenopausal Women Screened. Saudi Medical J, 2024, vol. 45 (11), pp. 1238–1244. DOI: 10.15537/smj.2024.45.11.20240571
31. Wetstein S.C., Onken A.M., Luffman C. et al. Deep learning assessment of breast terminal duct lobular unit involution: Towards automated prediction of breast cancer risk. PLoS One, 2020, vol. 15 (4). e0231653. DOI: 10.1371/journal.pone.0231653
32. de Bel T., Litjens G., Ogony J. et. al. Automated quantification of levels of breast terminal duct lobular (TDLU) involution using deep learning. JAWM. NPJ Breast Cancer, 2022, vol. 8 (1), p. 13. DOI: 10.1038/s41523-021-00378-7
33. Huo C.W., Chew G., Hill P. et al. High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res, 2015, vol. 17, p. 79.
34. Cecilia W. Huo. High mammographic density in women is associated with protumor inflammation. Breast Cancer Res, 2018, vol. 20 (1), p. 92.
35. Akrida I., Mulita F., Plachouri K.M. et al. Epithelial to mesenchymal transition (EMT) in metaplastic breast cancer and phyllodes breast tumors. Med. Oncol, 2023, vol. 41 (1), p. 20. DOI: 10.1007/s12032-023-02259-4
36. Gooding A.J., Schiemann W.P. Epithelial-Mesenchymal Transition Programs and Cancer Stem Cell Phenotypes: Mediators of Breast Cancer Therapy Resistance. Mol. Cancer Res., 2020, vol. 18 (9), pp. 1257–1270. DOI: 10.1158/1541-7786.MCR-20-0067
37. Javdani H., Mollaei H., Karimi F. et al. Review article epithelial to mesenchymal transition‑associated microRNAs in breast cancer. Mol. Biol. Rep, 2022, vol. 49 (10), pp. 9963–9973. DOI: 10.1007/s11033-022-07553-4
38. Abubakar M., Duggan M.A., Fan S. et al. Unraveling the role of stromal disruption in aggressive breast cancer etiology and outcomes. J. Natl. Cancer Inst, 2025, vol. 117 (8). — pp. 1673–1688. DOI: 10.1093/jnci/djaf070
39. Visscher D.W., Frost M.H., Hartmann L.C. et al. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. Cancer, 2016, vol. 122 (3), pp. 378–385. DOI: 10.1002/cncr.29766
40. Winters S., Martin C., Murphy D., Shokar N.K. Breast Cancer Epidemiology, Prevention, and Screening. Prog. Mol. Biol. Transl. Sci, 2017, vol. 151, pp. 1–32. DOI: 10.1016/bs.pmbts.2017.07.002
41. Dyrstad S.W., Yan Y., Fowler A.M., Colditz G.A. Breast cancer risk associated with benign breast disease: systematic review and meta-analysis. Breast Cancer Res. Treat, 2015, vol. 149 (3), pp. 569–575. DOI: 10.1007/s10549-014-3254-6
42. Personalized Autoantibody Profiling Distinguishes Early–stage Breast Cancer from Benign Disease January 2026 DOI:10.64898/2026.01.15.26344214 License CC BY-NC-ND 4.0.