Epigenetic regulation of breast cancer carcinogenesis

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Epigenetic mechanisms play a significant role in breast cancer (BC) pathogenesis and contribute to the tumor’s progression, metastasis and resistance to therapy. BC heterogeneity in large part is determined by unique epigenetic landscape created by various factors. However, despite obvious heterogeneity, modern therapeutic approaches in this disease are limited to evaluation of histological subtype, receptor status (estrogen, progesterone, human epidermal growth factor 2 receptors), and proliferative activity (Ki-67). All important oncogenes and tumor suppressor genes, as well as tumor microenvironment, are controlled by epigenetic factors, and study of these control mechanisms and identification of clinically significant epigenetic biomarkers is an important problem. Currently, there are thousands of studies on epigenetic regulation in BC, systematization of which will help to better understand complex mechanisms of carcinogenesis.

This review describes the main epigenetic mechanisms including DNA and RNA methylation, histone post-translational modification, and regulatory activity of non-coding RNAs. Characteristics of epigenetic regulation of various molecular and biological BC subtypes taking into account diagnostic and prognostic markers are analyzed, potential therapeutic targets are evaluated. The article also considers signaling pathways regulated by epigenetic modulators.

About the authors

E. R. Asanova

V.I. Vernadsky Crimean Federal University

Email: evgu79@mail.ru
ORCID iD: 0009-0001-0409-3297

Order of the Red Banner of Labor S.I. Georgievsky Medical Institute

Russian Federation, 5/7 Leninа Boulevard, Simferopol 295051

L. D. Khakimova

V.I. Vernadsky Crimean Federal University

Email: evgu79@mail.ru
ORCID iD: 0009-0002-7528-7598

Order of the Red Banner of Labor S.I. Georgievsky Medical Institute

Russian Federation, 5/7 Leninа Boulevard, Simferopol 295051

I. O. Golovkin

V.I. Vernadsky Crimean Federal University

Email: evgu79@mail.ru
ORCID iD: 0000-0002-3578-5130

Order of the Red Banner of Labor S.I. Georgievsky Medical Institute

Russian Federation, 5/7 Leninа Boulevard, Simferopol 295051

T. P. Makalish

V.I. Vernadsky Crimean Federal University

Email: evgu79@mail.ru
ORCID iD: 0000-0003-1884-2620

Order of the Red Banner of Labor S.I. Georgievsky Medical Institute

Russian Federation, 5/7 Leninа Boulevard, Simferopol 295051

E. Yu. Zyablitskaya

V.I. Vernadsky Crimean Federal University

Author for correspondence.
Email: evgu79@mail.ru
ORCID iD: 0000-0001-8216-4196

Order of the Red Banner of Labor S.I. Georgievsky Medical Institute

Russian Federation, 5/7 Leninа Boulevard, Simferopol 295051

References

  1. Kang Z., Wang J., Liu J. et al. Epigenetic modifications in breast cancer: from immune escape mechanisms to therapeutic target discovery. Front Immunol 2025;16:1584087. doi: 10.3389/fimmu.2025.1584087
  2. Trnkova L., Buocikova V., Mego M. et al. Epigenetic deregulation in breast cancer microenvironment: Implications for tumor progression and therapeutic strategies. Biomed Pharmacother 2024;174:116559. doi: 10.1016/j.biopha.2024.116559
  3. Sarkar S., Venkatesh D., Kandasamy T. et al. Epigenetic Modulations in Breast Cancer: An Emerging Paradigm in Therapeutic Implications. Front Biosci (Landmark Ed) 2024;29(8):287. doi: 10.31083/j.fbl2908287
  4. Pendina A.A., Grinkevich V.V., Kuznetsova T.V. et al. DNA methylation is a universal mechanism for regulating gene activity. Ekologicheskaya genetika = Ecological Genetics 2014;2(1):27–37. (In Russ.).
  5. Maksimova V.P., Usalka O.G., Makus J.V. et al. Aberrations of DNA methylation in cancer. Uspekhi molekulyar-noy onkologii = Advances in Molecular Oncology 2022;9(4):24–40. (In Russ.). doi: 10.17650/2313-805X-2022-9-4-24-40
  6. Wong K.K. DNMT1: a key drug target in triple-negative breast cancer. Seminars in Cancer Biology 2021;72:198–213. doi: 10.1016/j.semcancer.2020.05.010
  7. Kanwal R., Gupta S. Epigenetic modifications in cancer. Clin Genet 2012;81(4):303–11. doi: 10.1111/j.1399-0004.2011.01809.x
  8. Kazubskaya T.P., Loginov V.I., Khodyrev D.S. et al. Methylation of the RASSF1A, RARβ2, and SEMA3B genes in epithelial breast and ovarian tumors, and in patients with polyneoplasia. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of Female Reproductive System 2012;1:61–9. (In Russ.).
  9. Ryabchikov D.A., Vorotnikov I.K., Kazubskaya T.P. et al. Clinical assessment of the methylation profile of the promoter regions of 8 genes of chromosome 3 and the MGMT gene in luminal type of breast cancer. Rossiyskiy bioterapevticheskiy zhurnal = Russian Biotherapeutic Journal 2017;16(4):38–45. (In Russ.). doi: 10.17650/1726-9784-2017-16-4-38-45
  10. Smetannikova N.A., Abdurashitov M.A., Akishev A.G. et al. The use of GLAD-PCR analysis to study DNA methylation in the regulatory regions of oncosuppressor genes in breast cancer. Sibirskij onkologicheskij zhurnal = Siberian Journal of Oncology 2021;20(6):41–54. (In Russ.). doi: 10.21294/1814-4861-2021-20-6-41-54
  11. Li Z., Guo X., Wu Y. et al. Methylation profiling of 48 candidate genes in tumor and matched normal tissues from breast cancer patients. Breast Cancer Res Treat 2015;149(3):767–79. doi: 10.1007/s10549-015-3276-8
  12. De Almeida B.P., Apolónio J.D., Binnie A. et al. Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers. BMC Cancer 2019;19(1):219. doi: 10.1186/s12885-019-5403-0
  13. Krasny A.M., Kurevlev S.V., Sadekova A.A. et al. The profile of primary tumor gene methylation in patients with luminal HER2-negative breast cancer with metastasis to regional lymph nodes. Biomedicinskaya khimiya = Biomedical Chemistry 2021;67(1):88–94. (In Russ.). doi: 10.18097/PBMC20216701088
  14. Kalinkin A.I., Sigin V.O., Nemtsova M.V. et al. Determination of a prognostically significant DNA methylation signature in patients with various types of breast cancer. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta = Bulletin of the Russian State Medical University 2022;6:26–35. (In Russ.). doi: 10.24075/brsmu.2022.056
  15. Zhu C., Menyhart O., Győrffy B. et al. The prognostic association of SPAG5 gene expression in breast cancer patients with systematic therapy. BMC Cancer 2019;19(1):1046. doi: 10.1186/s12885-019-6260-6
  16. Dowling G.P., Daly G.R., Hegarty A. Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancers. Cancer Communications 2025;45(2):198–202. doi: 10.1002/cac2.12640
  17. Pirouzpanah S., Taleban F.A., Mehdipour P. et al. Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes. Cancer Biomarkers 2018;21(3):621–38. doi: 10.3233/CBM-170697
  18. Barbano R., Muscarella L.A., Pasculli B. et al. Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics 2013;8(1):105–12. doi: 10.4161/epi.23319
  19. Shukla V., Coumoul X., Lahusen T. et al. BRCA1 affects global DNA methylation through regulation of DNMT1. Cell Res 2010;20(11):1201–15. doi: 10.1038/cr.2010.128
  20. Turner N.C., Reis-Filho J.A., Russell A.M. et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007;26(14):2126–32. doi: 10.1038/sj.onc.1210014
  21. Menghi F., Banda K., Kumar P. et al. Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas. Sci Transl Med 2022;14(652):eabn1926. doi: 10.1126/scitranslmed.abn1926
  22. Yu R., Peng X., Cheng Z. et al. Promoter Hyper-methylation of ZNF662 restrains its tumor suppressing function in triple-negative breast cancer through regulating NGF signaling axis. Int J Biol Sci 2025;21(9):4081–97. doi: 10.7150/ijbs.102940
  23. Becker L.M., O’Connell J.T., Vo A.P. et al. Epigenetic Reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast. Cancer Cell Rep 2020;31(9):107701. doi: 10.1016/j.celrep.2020.107701
  24. Filippova E.A., Lukina S.S., Burdenny A.M. et al. Co-methylation in the coordinated regulation of a group of apoptosis genes in breast cancer. Patologicheskaya fiziologiya i eksperimental’naya terapiya = Pathological Physiology and Experimental Therapy, Russian Journal 2024;68(3):4–14. (In Russ.). doi: 10.25557/0031-2991.2024.03.4-14
  25. Qu G.Z., Grundy P.E., Narayan A. Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16. Cancer Genet Cytogenet 1999;109(1):34–39. doi: 10.1016/s0165-4608(98)00143-5
  26. Downs B., Wang S.M. Epigenetic changes in BRCA1-mutated familial breast cancer. Cancer Genet 2015;208(5):237–40. doi: 10.1016/j.cancergen.2015.02.001
  27. Ansar M., Thu L.T.A., Hung C.S. et al. Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer. Front Oncol 2022;12:1004261. doi: 10.3389/fonc.2022.1004261
  28. Skaar D.A., Dietze E.C., Alva-Ornelas J.A. et al. Epigenetic dysregulation of kcnk9 imprinting and triple-negative breast cancer. Cancers (Basel) 2021;13(23):6031. doi: 10.3390/cancers13236031
  29. Mendaza S., Ulazia-Garmendia A., Monreal-Santesteban I. et al. ADAM12 is a potential therapeutic target regulated by hypomethylation in triple-negative breast cancer. Int J Mol Sci 2020;21(3):903. doi: 10.3390/ijms21030903
  30. Kim Y., Ko J.Y., Kong H.K. et al. Hypomethylation of ATP1A1 Is associated with poor prognosis and cancer progression in triple-negative breast cancer. Cancers (Basel) 2024;16(9):1666. doi: 10.3390/cancers16091666
  31. Ranga S., Yadav R., Chauhan M. et al. Modifications of RNA in cancer: a comprehensive review. Mol Biol Rep 2025;52(1):321. doi: 10.1007/s11033-025-10419-0
  32. Li Y., Jin H., Li Q. et al. The role of RNA methylation in tumor immunity and its potential in immunotherapy. Mol Cancer 2024;23(1):130. doi: 10.1186/s12943-024-02041-8
  33. Roundtree I.A., Evans M.E., Pan T., He C. Dynamic RNA modifications in gene expression regulation. Cell 2017;169:1187–200. doi: 10.1016/j.cell.2017.05.045
  34. Yang L., Wu S., Ma C. et al. RNA m6A methylation regulators subclassify luminal subtype in breast cancer. Front Oncol 2021;10:611191. doi: 10.3389/fonc.2020.611191
  35. Shi Z., Cao X., Ma Y. et al. RNA methyltransferase METTL16: from molecular mechanisms to therapeutic prospects in cancers. Cancer Lett 2025;624:217698. doi: 10.1016/j.canlet.2025.217698
  36. Dai Y., Zhao S., Chen H. et al. RNA methylation and breast cancer: insights into m6A, m7G and m5C. Mol Biol Rep 2024;52(1):27. doi: 10.1007/s11033-024-10138-y
  37. Huang S., Lin Y., Liu X. et al. Single-cell analysis reveal cell-type-specific RNA methylation patterns in breast cancer. J Int Med Res 2025;53(12):3000605251405638. doi: 10.1177/03000605251405638
  38. Marcel V., Kielbassa J., Marchand V. et al. Ribosomal RNA 2’O-methylation as a novel layer of inter-tumour heterogeneity in breast cancer. NAR Cancer 2020;2(4):zcaa036. doi: 10.1093/narcan/zcaa036
  39. Xiong J., Zhou Z., Jiang Y. et al. Hypoxic stabilization of RIPOR3 mRNA via METTL3-mediated m(6)A methylation drives breast cancer progression and metastasis. Oncogene 2024;43(47):3426–41. doi: 10.1038/s41388-024-03180-4
  40. Acharjee S., Chauhan S., Pal R. et al. Mechanisms of DNA methylation and histone modifications. Prog Mol Biol Transl Sci 2023;97:51–92. doi: 10.1016/bs.pmbts.2023.01.001
  41. Zaib S., Rana N., Khan I. Histone modifications and their role in epigenetics of cancer. Curr Med Chem 2022;29(14):2399–411. doi: 10.2174/0929867328666211108105214
  42. Bannister A.J., Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011;21(3):381–95. doi: 10.1038/cr.2011.22
  43. Garraway L.A., Lander E.S. Lessons from the cancer genome. Cell 2013;153(1):17–37. doi: 10.1016/j.cell.2013.03.002
  44. Audia J.E., Campbell R.M. Histone modifications and cancer. Cold Spring Harb Perspect Biol 2016;8(4):a019521. doi: 10.1101/cshperspect.a019521
  45. Spange S., Wagner T., Heinzel T. et al. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 2009;41(1):185–98. doi: 10.1016/j.biocel.2008.08.027
  46. Gajer J.M., Furdas S.D., Grunder A. et al. Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo. Oncogenesis 2015;4(2):e137. doi: 10.1038/oncsis.2014.51
  47. Fermento M.E., Gandini N.A., Lang C.A. et al. Intracellular distribution of p300 and its differential recruitment to aggresomes in breast cancer. Exp Mol Pathol 2010;88(2):256–64. doi: 10.1016/j.yexmp.2010.01.007
  48. Yang H., Pinello C.E., Luo J. et al. Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents. Mol Cancer Ther 2013;12(5):610–20. doi: 10.1158/1535-7163.MCT-12-0930
  49. Liu Z., Luo X., Liu L. et al. Histone acetyltransferase p300 promotes MKL1-mediated transactivation of catechol-O-methyltransferase gene. Acta Biochim Biophys Sin (Shanghai) 2013;45(12):1002–10. doi: 10.1093/abbs/gmt108
  50. Shan W., Jiang Y., Yu H. et al. HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer. Am J Cancer Res 2017;7(5):1213–26.
  51. Li Y., Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med 2016;6(10):a026831. doi: 10.1101/cshperspect.a026831
  52. Mehmood S.A., Sahu K.K., Sengupta S. et al. Recent advancement of HDAC inhibitors against breast cancer. Med Oncol 2023;40(7):201. doi: 10.1007/s12032-023-02058-x
  53. Park S.Y., Jun J.A., Jeong K.J. et al. Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep 2011;25(6):1677–81. doi: 10.3892/or.2011.1236
  54. Cutano V., Di Giorgio E., Minisini M. et al. HDAC7-mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells. Mol Oncol 2019;13(8):1651–68. doi: 10.1002/1878-0261.12503
  55. Salgado E., Bian X., Feng A. et al. HDAC9 overexpression confers invasive and angiogenic potential to triple negative breast cancer cells via modulating microRNA-206. Biochem Biophys Res Commun 2018;503(2):1087–91. doi: 10.1016/j.bbrc.2018.06.120
  56. Debbarma M., Sarkar K., Sil S.K. Dissecting the epigenetic orchestra of HDAC isoforms in breast cancer development: a review. Med Oncol 2024;42(1):1. doi: 10.1007/s12032-024-02553-9
  57. Su Y., Hopfinger N.R., Nguyen T.D. et al. Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors. J Exp Clin Cancer Res 2018;37(1):314. doi: 10.1186/s13046-018-0988-8
  58. Cao Y.N., Li X.H., Chen X.J. et al. Identification of eight histone methylation modification regulators associated with breast cancer prognosis. IET Syst Biol 2025;19(1):e70012. doi: 10.1049/syb2.70012
  59. Katz T.A., Huang Y., Davidson N.E. et al. Epigenetic reprogramming in breast cancer: from new targets to new therapies. Ann Med 2014;46(6):397–408. doi: 10.3109/07853890.2014.923740
  60. Michalak E.M., Visvader J.E. Dysregulation of histone methyltransferases in breast cancer - Opportunities for new targeted therapies? Mol Oncol 2016;10(10):1497–515. doi: 10.1016/j.molonc.2016.09.003
  61. Adibfar S., Elveny M., Kashikova H.S. et al. The molecular mechanisms and therapeutic potential of EZH2 in breast cancer. Life Sci 2021;286:120047. doi: 10.1016/j.lfs.2021.120047
  62. Byun W.S., Kim W.K., Han H.J. et al. Targeting histone methyltransferase dot1l by a novel psammaplin a analog inhibits growth and metastasis of triple-negative breast cancer. Mol Ther Oncolytics 2019;15:140–52. doi: 10.1016/j.omto.2019.09.005
  63. Serce N., Gnatzy A., Steiner S. et al. Elevated expression of LSD1 (lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol 2012;12:13. doi: 10.1186/1472-6890-12-13
  64. Martinez S., Sentis S., Poulard C. et al. Role of PRMT1 and PRMT5 in breast cancer. Int J Mol Sci 2024;25(16):8854. doi: 10.3390/ijms25168854
  65. Li J., Chen Z., Jin M. et al. Histone H4K12 lactylation promotes malignancy progression in triple-negative breast cancer through SLFN5 downregulation. Cell Signal 2024;124:111468. doi: 10.1016/j.cellsig.2024.111468
  66. Nair M.G., Somashekaraiah V.M., Ramamurthy V. et al. miRNAs: critical mediators of breast cancer metastatic programming. Exp Cell Res 2021;401(1):112518. doi: 10.1016/j.yexcr.2021.112518
  67. Wang C., Zheng X., Shen C. et al. MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells. J Exp Clin Cancer Res 2012;31(1):58. doi: 10.1186/1756-9966-31-58
  68. Braga E.A., Burdennyy A.M., Pronina I.V. et al. System of markers based on the methylation of a group of proapoptotic genes in combination with microRNA in the diagnosis of breast cancer. Bull Exp Biol Med 2020;168(3):366–70. doi: 10.1007/s10517-020-04710-2
  69. Ryabchicov D.A., Dudina I.A., Vorotnikov I.K. et al. The role of microRNA genes methylation in different molecular-biological subtypes of breast cancer. Zlokachestvennye opukholi = Malignant Tumours 2018;8(1):5–11. (In Russ.). doi: 10.18027/2224-5057-2018-8-1-5-11
  70. Hu H., Li S., Cui X. et al. The overexpression of hypomethylated MiR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2). J Biol Chem 2013;288(16):10973–85. doi: 10.1074/jbc.M112.434340
  71. Hu J., Yi T., Chu S. et al. DNA methylation of miR-93: an important event in acquiring drug resistance in breast cancer cells. Int J Clin Exp Med 2019;12(5):4697–706.
  72. Kim J., Siverly A.N., Chen D. et al. Ablation of miR-10b suppresses oncogene-induced mammary tumorigenesis and metastasis and reactivates tumor-suppressive pathways. Cancer Res 2016;76(21):6424–35. doi: 10.1158/0008-5472.CAN-16-1571
  73. Ren L., Chen H., Song J. et al. MiR-454-3p-mediated Wnt/β-catenin signaling antagonists suppression promotes breast cancer metastasis. Theranostics 2019;9(2):449–65. doi: 10.7150/thno.29055
  74. Liu L.Z., Li C., Chen Q. et al. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS One 2011;6(4):e19139. doi: 10.1371/journal.pone.0019139
  75. Koyama Y., Muguruma M., Horimoto Y. et al. Hsa-miR-155-5p expression in primary breast tissue may have the potential for prediction of breast cancer brain recurrence: results from the multi-institutional exploratory cohort study. Breast Cancer Res 2025;27(1):169. doi: 10.1186/s13058-025-02123-5
  76. Balashenko N.A., Dromashko S.E. Long non-coding RNAs and their functions. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya biyalagichnych navuk = Proceedings of the National Academy of Sciences of Belarus. Biological series 2017;4:110–19. (In Russ.).
  77. Zheng X., Zhang S., Ma H. et al. Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer. Mol Cell Endocrinol 2024;592:112321. doi: 10.1016/j.mce.2024.112321
  78. Ghafouri-Fard S., Tamizkar K.H., Hussen B.M., Taheri M. An update on the role of long non-coding RNAs in the pathogenesis of breast cancer. Pathol Res Pract 2021;219:153373. doi: 10.1016/j.prp.2021.153373
  79. Kansara S., Pandey V., Lobie P.E. et al. Mechanistic involvement of long non-coding RNAs in oncotherapeutics resistance in triple-negative breast. Cancer Cells 2020;9(6):1511. doi: 10.3390/cells9061511
  80. Lee J.J., Kim M., Kim H.P. Epigenetic regulation of long noncoding RNA UCA1 by SATB1 in breast cancer. BMB Rep 2016;49(10):578–83. doi: 10.5483/bmbrep.2016.49.10.156
  81. Chen X., Luo R., Zhang Y. et al. Long noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer. Nat Commun 2022;13(1):7160. doi: 10.1038/s41467-022-34702-x
  82. Bai Z., Zhang Y., Li J. et al. Epigenetic regulation of GFRA1 by extracellular vesicle lncRNA SOX9-AS1 facilitates breast cancer metastasis. FASEB J 2025;39(12):e70642. doi: 10.1096/fj.202403246R
  83. Zhang Y., Wei S., Chen Z. et al. LncRNA FAISL Inhibits calpain 2-mediated proteolysis of FAK to promote progression and metastasis of triple negative breast cancer. Adv Sci (Weinh) 2024;11(42):e2407493. doi: 10.1002/advs.202407493
  84. Farzaneh M., Najafi S., Dari M.A.G. et al. Functional roles of long noncoding RNA MALAT1 in gynecologic cancers. Clin Transl Oncol 2023;25(1):48–65. doi: 10.1007/s12094-022-02914-8
  85. Filippova E.A., Fridman M.V., Burdennyy A.M. et al. Long noncoding RNA GAS5 in breast cancer: epigenetic mechanisms and biological functions. Int J Mol Sci 2021;22(13):6810. doi: 10.3390/ijms22136810
  86. Hussain M.S., Majami A.A., Ali H. et al. The complex role of MEG3: an emerging long non-coding RNA in breast cancer. Pathol Res Pract 2023;251:154850. doi: 10.1016/j.prp.2023.154850
  87. Zhang Y., Dong X., Guo X. et al. LncRNA-BC069792 suppresses tumor progression by targeting KCNQ4 in breast cancer. Mol Cancer 2023;22(1):41. doi: 10.1186/s12943-023-01747-5
  88. Keyvani-Ghamsari S., Khorsandi K., Rasul A. et al. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021;13(1):120. doi: 10.1186/s13148-021-01107-4
  89. Grebennikova T.A., Belaya Zh.E., Rozhinskaya L.Ya. et al. The canonical Wnt/β-catenin signaling pathway: from the history of discovery to clinical application. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta = Therapeutic Archive 2016;88(10):74–81. (In Russ.).
  90. Klarmann G.J., Decker A., Farrar W.L. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics 2008;3(2):59–63. doi: 10.4161/epi.3.2.5899
  91. Jang G.B., Kim J.Y., Cho S.D. et al. Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 2015;5:12465. doi: 10.1038/srep12465
  92. Wang Y., He L., Du Y. et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 2015;16(4):413–25. doi: 10.1016/j.stem.2015.03.003
  93. Wils L.J., Bijlsma M.F. Epigenetic regulation of the Hedgehog and Wnt pathways in cancer. Crit Rev Oncol Hematol 2018;121:23–44. doi: 10.1016/j.critrevonc.2017.11.013
  94. Lindvall C., Bu W., Williams B.O. et al. Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 2007;3(2):157–68. doi: 10.1007/s12015-007-0025-3
  95. Zasadkevich Yu.M., Brilliant A.A., Sazonov S.V. The role of cadherins in the norm and in the development of breast cancer. Arkhiv patologii = Archive of Pathology 2015;77(3):57–64. (In Russ.). doi: 10.17116/patol201577357-64
  96. Geyer F.C., Lacroix-Triki M., Savage K. et al. β-catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol 2011;24(2):209–31. doi: 10.1038/modpathol.2010.205
  97. Cui J., Li P., Liu X. et al. Abnormal expression of the Notch and Wnt/β-catenin signaling pathways in stem-like ALDHhiCD44+ cells correlates highly with Ki-67 expression in breast cancer. Oncol Lett 2015;9(4):1600–6. doi: 10.3892/ol.2015.2942
  98. Hashizume R., Koizumi H., Ihara A. et al. Expression of beta-catenin in normal breast tissue and breast carcinoma: a comparative study with epithelial cadherin and alpha-catenin. Histopathology 1996;29(2):139–46. doi: 10.1046/j.1365-2559.1996.d01-499.x
  99. Qureshi H.S., Linden M.D., Divine G. et al. E-cadherin status in breast cancer correlates with histologic type but does not correlate with established prognostic parameters. Am J Clin Pathol 2006;125(3):377–85. doi: 10.1309/wmx7drwtfvqp2lqt
  100. Shi Y., Liu X., Sun Y. et al. Decreased expression and prognostic role of EHD2 in human breast carcinoma: correlation with E-cadherin. J Mol Histol 2015;46(2):221–31. doi: 10.1007/s10735-015-9614-7
  101. Crea F., Danesi R., Farrar W.L. Cancer stem cell epigenetics and chemoresistance. Epigenomics 2009;1(1):63–79. doi: 10.2217/epi.09.4.
  102. Duan Z.H., Wang H.C., Zhao D.M. et al. Cooperatively transcriptional and epigenetic regulation of sonic hedgehog overexpression drives malignant potential of breast cancer. Cancer Sci 2015;106(8):1084–91. doi: 10.1111/cas.12697
  103. Samadani A.A., Norollahi S.E., Rashidy-Pour A. et al. Cancer signaling pathways with a therapeutic approach: An overview in epigenetic regulations of cancer stem cells. Biomed Pharmacother 2018;108:590–9. doi: 10.1016/j.biopha.2018.09.048
  104. Hui M., Cazet A., Nair R. et al. The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy. Breast Cancer Res 2013;15(2):203. doi: 10.1186/bcr3401
  105. Fiaschi M., Rozell B., Bergström A. et al. Targeted expression of GLI1 in the mammary gland disrupts pregnancy-induced maturation and causes lactation failure. J Biol Chem 2007;282(49):36090–101. doi: 10.1074/jbc.M704280200
  106. Keyvani-Ghamsari S., Khorsandi K., Rasul A. et al. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021;13(1):120. doi: 10.1186/s13148-021-01107-4
  107. Ponnusamy L., Mahalingaiah P.K.S., Chang Y.W. et al. Role of cellular reprogramming and epigenetic dysregulation in acquired chemoresistance in breast cancer. Cancer Drug Resist 2019;2(2):297–312. doi: 10.20517/cdr.2018.11
  108. Brabletz S., Bajdak K., Meidhof S. et al. The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J 2011;30(4):770–82. doi: 10.1038/emboj.2010.349
  109. Yousefi H., Bahramy A., Zafari N. et al. Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer. BMC Cancer 2022;22(1):1282. doi: 10.1186/s12885-022-10383-z
  110. Chow E.K., Fan L.L., Chen X. et al. Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. Hepatology 2012;56(4):1331–41. doi: 10.1002/hep.25776
  111. Wang X., Low X.C., Hou W. et al. Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells. ACS Nano 2014;8(12):12151–66. doi: 10.1021/nn503491e
  112. Wang K., Zhang Q., Li D. et al. PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor. Clin Cancer Res 2015;21(6):1487–96. doi: 10.1158/1078-0432.CCR-14-1348
  113. Stylianou S., Clarke R.B., Brennan K. Aberrant activation of notch signaling in human breast cancer. Cancer Res 2006;66(3):1517–25. doi: 10.1158/0008-5472.CAN-05-3054
  114. Nandi A., Chakrabarti R. The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance. Genes Dev 2020;34(21–22):1422–38. doi: 10.1101/gad.342287.120
  115. Li L., Luo J., Fang J.Y. et al. Expression characteristics of the yes-associated protein in breast cancer: a meta-analysis. Medicine (Baltimore) 2022;101(34):e30176. doi: 10.1097/MD.0000000000030176
  116. Bai J., Xi Q. Crosstalk between TGF-β signaling and epigenome. Acta Biochim Biophys Sin (Shanghai) 2018;50(1):60–7. doi: 10.1093/abbs/gmx122
  117. Wiercinska E., Naber H.P., Pardali E. et al. The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat 2011;128(3):657–66. doi: 10.1007/s10549-010-1147-x
  118. Zhang X., Powell K., Li L. Breast cancer stem cells: biomarkers, identification and isolation methods, regulating mechanisms, cellular origin, and beyond. Cancers (Basel) 2020;12(12):3765. doi: 10.3390/cancers12123765
  119. Subhadarshini S., Markus J., Sahoo S. et al. Dynamics of epithelial-mesenchymal plasticity: what have single-cell investigations elucidated so far? ACS Omega 2023;8(13):1166–73. doi: 10.1021/acsomega.2c07989
  120. Cho M.H., Park J.H., Choi H.J. et al. DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression. Nat Commun 2015;6:7821. doi: 10.1038/ncomms8821
  121. Liu J., Sun X., Qin S. et al. CDH1 promoter methylation correlates with decreased gene expression and poor prognosis in patients with breast cancer. Oncol Lett 2016;11(4):2635–43. doi: 10.3892/ol.2016.4274
  122. Bücker L., Lehmann U. CDH1 (E-cadherin) gene methylation in human breast cancer: critical appraisal of a long and twisted story. Cancers (Basel) 2022;14(18):4377. doi: 10.3390/cancers14184377
  123. Simonova O.A., Kuznetsova E.B., Tanas A.S. et al. Methylation of genes of extracellular matrix proteins and transmembrane receptors is normal and in breast cancer. Medicinskaya genetika = Medical Genetics 2020;19(6):24–5. (In Russ.).
  124. Zuo X.X., Yang Y., Zhang Y. et al. Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway. Cell Commun Signal 2019;17(1):142. doi: 10.1186/s12964-019-0464-x
  125. Bakr N.M., Mahmoud M.S., Nabil R. et al. Impact of circulating miRNA-373 on breast cancer diagnosis through targeting VEGF and cyclin D1 genes. J Genet Eng Biotechnol 2021;19(1):84. doi: 10.1186/s43141-021-00174-7
  126. Peng F., Xiong L., Tang H. et al. Regulation of epithelial-mesenchymal transition through microRNAs: clinical and biological significance of microRNAs in breast cancer. Tumour Biol 2016;37(11):14463–77. doi: 10.1007/s13277-016-5334-1
  127. Zhao M., Ang L., Huang J. et al. MicroRNAs regulate the epithelial-mesenchymal transition and influence breast cancer invasion and metastasis. Tumour Biol 2017;39(2):1010428317691682. doi: 10.1177/1010428317691682
  128. Studenikina A.A., Arkhipov S.A., Zhurakovsky I.P. et al. Expression of markers of the epithelial-mesenchymal transition in breast cancer. Arkhiv pathologii = Archive of Pathology 2023;85(4):12–7. (In Russ.).
  129. Wang Z., Li Y., Kong D. et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res 2009;69(6):2400–7. doi: 10.1158/0008-5472.CAN-08-4312
  130. Shukla S., Meeran S.M. Epigenetics of cancer stem cells: Pathways and therapeutics. Biochim Biophys Acta 2014;1840(12):3494–502. doi: 10.1016/j.bbagen.2014.09.017
  131. Smythies J. Intercellular signaling in cancer-the SMT and TOFT hypotheses, exosomes, telocytes and metastases: is the messenger in the message? J Cancer 2015;6(7):604–9. doi: 10.7150/jca.12372
  132. Anderson N.M., Simon M.C. The tumor microenvironment. Curr Biol 2020;30(16):R921–5. doi: 10.1016/j.cub.2020.06.081
  133. Wong W.K., Yin B., Lam C.Y.K. et al. The Interplay between epigenetic regulation and CD8+ T cell differentiation/exhaustion for T Cell Immunotherapy. Front Cell Dev Biol 2022;9:783227. doi: 10.3389/fcell.2021.783227
  134. Yang X., Wang X., Liu D. et al. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol 2014;28(4):565–74. doi: 10.1210/me.2013-1293
  135. Saleh R., Toor S.M., Sasidharan Nair V. et al. Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression. Front Immunol 2020;11:1469. doi: 10.3389/fimmu.2020.01469
  136. Dai E., Zhu Z., Wahed S. et al. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer 2021;20(1):171. doi: 10.1186/s12943-021-01464-x
  137. Yao Y., Qian R., Gao H. et al. LSD1 deficiency in breast cancer cells promotes the formation of pre-metastatic niches. NPJ Precis Oncol 2024;8(1):260. doi: 10.1038/s41698-024-00751-2
  138. Liu X., Wu X., Ding J. et al. Advances in the epigenetic regulation of breast cancer. Chin Med J (Engl) 2025;138(24):3302–16. doi: 10.1097/CM9.0000000000003890

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2026 ABV-Press

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-57560 от  08.04.2014.