Роль LINE-ретроэлементов в развитии рака молочной железы

Mustafin, R. N. (2026). The role of LINE retroelements in breast cancer development. Voprosy Onkologii, 72(1), OF–2368. https://doi.org/10.37469/0507-3758-2026-72-1-OF-2368

Abstract

Breast cancer is the most common malignant neoplasm in the world. In 5–15% of cases, the disease is monogenic, caused by heterozygous germline mutations in the BRCA1, BRCA2, ATM, BARD1, CHEK2, RAD51D, RAD51C, PALB2 genes. Most cases of breast cancer are multifactorial diseases associated with multiple SNPs, many of which are located in intergenic and intronic regions where retroelement genes and non-coding RNA genes derived from them are located. The most common retroelements in the human genome are LINEs, the activation of which in breast cancer has been identified in a number of scientific publications. The mechanisms of LINE influence on breast cancer carcinogenesis due to activation of genomic instability, chromoanagenesis, formation of oncogenes and inactivation of tumor suppressors are described. It can be assumed that SNPs associated with breast cancer exert their influence on cancer development by changing the properties of LINEs and microRNAs interacting with them. An analysis of scientific literature confirms this assumption: in breast cancer, change in 17 oncogenic microRNAs derived from retroelements expression has been identified, which can be used as targets for targeted antitumor therapy. In addition, 21 tumor suppressor LINE-derived microRNAs that are promising for the treatment of breast cancer have been described. The interaction of LINE-derived microRNAs with 8 long non-coding RNAs, in the evolution of which retroelements also play a key role, is also described. Investigation of these data may reveal new mechanisms of breast cancer pathogenesis involving LINEs, long non-coding RNAs and microRNAs.

https://doi.org/10.37469/0507-3758-2026-72-1-OF-2368

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References

Злокачественные новообразования в России в 2020 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М. 2021: 252. [Malignant neoplasms in Russia in 2020 (morbidity and mortality). Ed. by Kaprin A.D., Starnisky V.V., Shakhzadova A.O. Moscow. 2021: 252 (in Rus)].

Sokolova A., Johnstone K.J., McCart Reed A.E., et al. Hereditary breast cancer: syndromes, tumour pathology and molecular testing. Histopathology. 2023; 82(1): 70-82.-DOI: https://doi.org/10.1111/his.14808.

Мустафин Р.Н., Хуснутдинова Э.К. Роль ретроэлементов в развитии наследственных опухолевых синдромов. Успехи молекулярной онкологии. 2021; 4: 42-52.-DOI: https://doi.org/10.17650/2313-805X-2021-8-4-42-52. [Mustafin R.N., Khusnutdinova E.K. The role of retroelements in the development of hereditary tumor syndromes. Advances in Molecular Oncology. 2021; 4: 42-52.-DOI: https://doi.org/10.17650/2313-805X-2021-8-4-42-52 (In Rus)].

Yu C., Zhang T., Chen F., Yu Z. The impact of hsa-miR-1972 on the expression of von Willebrand factor in breast cancer progression regulation. Peer J. 2024; 12: e18476.-DOI: https://doi.org/10.7717/peerj.18476.

Turashvili G., Lightbody E.D., Tyryshkin K., et al. Novel prognostic and predictive microRNA targets for triple-negative breast cancer. FASEB J. 2018: fj201800120R.-DOI: https://doi.org/10.1096/fj.201800120R.

Michailidou K., Beesley J., Lindstrom S., et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet. 2015; 47(4): 373-80.-DOI: https://doi.org/10.1038/ng.3242.

Zhang H., Ahearn T.U., Lecarpentier J., et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet. 2020; 52(6): 572-581.-DOI: https://doi.org/10.1038/s41588-020-0609-2.

Yong S.Y., Raben T.G., Lello L., Hsu S.D.H. Genetic architecture of complex traits and disease risk predictors. Sci Rep. 2020; 10(1): 12055.-DOI: https://doi.org/10.1038/s41598-020-68881-8.

Nurk S., Koren S., Rhie A., et al. The complete sequence of a human genome. Science. 2022; 376(6588): 44-53.-DOI: https://doi.org/10.1126/science.abj6987.

Mustafin R.N. The role of transposable elements in the association of polymorphic variants with multifactorial diseases. Opera Medica et Physiologica. 2024; 11(4): 60-70.-DOI: https://doi.org/10.24412/2500-2295-2024-4-60-70.

Park E.G., Ha H., Lee D.H., et al. Genomic analyses of non-coding RNAs overlapping transposable elements and its implication to human diseases. Int J Mol Sci. 2022; 23(16): 8950.-DOI: https://doi.org/10.3390/ijms23168950.

Zabihi N., Sadeghi S., Tabatabaeian H., et al. The association between rs1972820 and the risk of breast cancer in Isfahan population. J Cancer Res Ther. 2017; 13(1): 26-32.-DOI: https://doi.org/10.4103/0973-1482.183202.

Jang H.S., Shah N.M., Du A.Y., et al. Transposable elements drive widespread expression of oncogenes in human cancer. Nat Genet. 2019; 51: 611-617.-DOI: https://doi.org/10.1038/s41588-019-0373-3.

Rodriguez-Martin B., Alvarez E.G., Baez-Ortega A., et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat Genet. 2020; 52: 306-319.-DOI: https://doi.org/10.1038/s41588-019-0562-0.

Kankava K., Kvaratskhelia E., Burkadze G., et al. LINE-1 methylation in blood and tissues of patients with breast cancer. Georgian Med News. 2018; 276: 107-112.

Van Hoesel A.Q., van de Velde C.J.H., Kuppen P.J.K., et al. Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study. Breast Cancer Res Treat. 2012; 134(3): 1103-14.-DOI: https://doi.org/10.1007/s10549-012-2038-0.

Park S.Y., Seo A.N., Jung H.Y., et al. Alu and LINE-1 hypomethylation is associated with HER2 enriched subtype of breast cancer. PLoS One. 2014; 9(6): e100429.-DOI: https://doi.org/10.1371/journal.pone.0100429.

Jiang J.C., Rothnagel J.A., Upton K.R. Widespread exaptation of L1 transposons for transcription factor binding in breast cancer. Int J Mol Sci. 2021; 22(11): 5625.-DOI: https://doi.org/10.3390/ijms22115625.

Berrino E., Miglio U., Bellomo S.E., et al. The tumor-specific expression of L1 retrotransposons independently correlates with time to relapse in hormone-negative breast cancer patients. Cells. 2022; 11(12): 1944.-DOI: https://doi.org/10.3390/cells11121944.

Ramos K.S., Montoya-Durango D.E., Teneng I., et al. Epigenetic control of embryonic renal cell differentiation by L1 retrotransposon. Birth Defects Res A Clin Mol Teratol. 2011; 91(8): 693-702.-DOI: https://doi.org/10.1002/bdra.20786.

Shukla R., Upton K.R., Munoz-Lopez, et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 2013; 153(1): 101-11.-DOI: https://doi.org/10.1016/j.cell.2013.02.032.

Xia Z., Cochrane D.R., Anglesio M.S., et al. LINE-1 retrotransposon-mediated DNA transductions in endometriosis associated ovarian cancer. Gynecol Oncol. 2017; 147(3): 642-647.-DOI: https://doi.org/10.1016/j.ygyno.2017.09.032.

Cajuso T., Sulo P., Tanskanen T., et al. Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival. Nat Commun. 2019; 10(1): 4022.-DOI: https://doi.org/10.1038/s41467-019-11770-0.

Aschacher T., Wolf B., Enzmann F., et al. LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines. Oncogene. 2016; 35(1): 94-104.-DOI: https://doi.org/10.1038/onc.2015.65.

Nair M.G., Ramesh R.S., Naidu C.M., et al. Estimation of ALU repetitive elements in plasma as a cost-effective liquid biopsy tool for disease prognosis in breast cancer. Cancers (Basel). 2023; 15(4): 1054.-DOI: https://doi.org/10.3390/cancers15041054.

Мустафин Р.Н. Участие ретроэлементов в хромоанагенезе при развитии злокачественных новообразований. Сибирский онкологический журнал. 2024; 23(5): 146-156.-DOI: https://doi.org/10.21294/1814-4861-2024-23-5-146-156. [Mustafin R.N. Participation of retroelements in chromoanagenesis in cancer development. Siberian Journal of Oncology. 2024; 23(5): 146-156.-DOI: https://doi.org/10.21294/1814-4861-2024-23-5-146-156 (In Rus)].

Bolkestein M., Wong J.K.L., Thewes V., et al. Chromothripsis in human breast cancer. Cancer Res. 2020; 80(22): 4918-4931.-DOI: https://doi.org/10.1158/0008-5472.CAN-20-1920.

Vasmatzis G., Wang X., Smadbeck J.B., et al. Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples. BMC Cancer. 2018; 18(1): 738.-DOI: https://doi.org/10.1186/s12885-018-4594-0.

Мустафин Р.Н., Хуснутдинова Э.К. Некодирующие части генома как основа эпигенетической наследственности. Вавиловский журнал генетики и селекции. 2017; 21(6): 742-749.-DOI: https://doi.org/10.18699/VJ17.30-o. [Mustafin R.N., Khusnutdinova E.K. Non-coding parts of genomes as the basis of epigenetic heredity. Vavilov Journal of Genetics and Breeding. 2017; 21(6): 742-749.-DOI: https://doi.org/10.18699/VJ17.30-o (in Rus)].

Petri R., Brattås P.L., Sharma Y., et al. LINE-2 transposable elements are a source of functional human microRNAs and target sites. PLoS Genet. 2019; 15(3): e1008036.-DOI: https://doi.org/10.1371/journal.pgen.1008036.

Moro J., Grinpelc A., Farré P.L., et al. miR-877-5p as a potential link between triple-negative breast cancer development and metabolic syndrome. Int J Mol Sci. 2023; 24(23): 16758.-DOI: https://doi.org/10.3390/ijms242316758.

Chen Z., Gong X., Cheng C., et al. Circ_0001777 affects triple-negative breast cancer progression through the miR-95-3p/AKAP12 Axis. Clin Breast Cancer. 2023; 23(2): 143-154.-DOI: https://doi.org/10.1016/j.clbc.2022.11.004.

Yusof K.M., Groen K., Rosli R., et al. Evaluation of circulating microRNAs and adipokines in breast cancer survivors with arm lymphedema. Int J Mol Sci. 2022; 23(19): 11359.-DOI: https://doi.org/10.3390/ijms231911359.

Wang Y., Yin W., Lin Y., et al. Downregulated circulating microRNAs after surgery: potential noninvasive biomarkers for diagnosis and prognosis of early breast cancer. Cell Death Discov. 2018; 4: 21.-DOI: https://doi.org/10.1038/s41420-018-0089-7.

Wang H., Hu X., Yang F., Xiao H. miR-325-3p Promotes the proliferation, invasion, and EMT of breast cancer cells by directly targeting S100A2. Oncol Res. 2021; 28(7): 731-744.-DOI: https://doi.org/10.3727/096504020X16100888208039.

Jiang B., Xia J., Zhou X. Overexpression of lncRNA SLC16A1-AS1 suppresses the growth and metastasis of breast cancer via the miR-552-5p/WIF1 signaling pathway. Front Oncol. 2022; 12: 712475.-DOI: https://doi.org/10.3389/fonc.2022.712475.

Li D., Hu A. LINC-PINT suppresses breast cancer cell proliferation and migration via MEIS2/PPP3CC/NF-κB pathway by sponging miR-576-5p. Am J Med Sci. 2024; 367(3): 201-211. https://doi.org/10.1016/j.amjms.2023.08.013.

Zeng X., Ma X., Guo H. et al. MicroRNA-582-5p promotes triple-negative breast cancer invasion and metastasis by antagonizing CMTM8. Bioengineered. 2021; 12(2): 10126-10135.-DOI: https://doi.org/10.1080/21655979.2021.2000741.

Yuan C. miR-616 promotes breast cancer migration and invasion by targeting TIMP2 and regulating MMP signaling. Oncol Lett. 2019; 18(3): 2348-2355.-DOI: https://doi.org/10.3892/ol.2019.10546.

Wang B., Wang Y., Wang X., et al. Extracellular vesicles carrying miR-887-3p promote breast cancer cell drug resistance by targeting BTBD7 and activating the Notch1/Hes1 signaling pathway. Dis Markers. 2022; 2022: 5762686.-DOI: https://doi.org/10.1155/2022/5762686.

Turkistani S., Sugita B.M., Fadda P., et al. A panel of miRNAs as prognostic markers for African-American patients with triple negative breast cancer. BMC Cancer. 2021; 21(1): 861.-DOI: https://doi.org/10.1186/s12885-021-08573-2.

He Y.Y., Xiao B., Qiu J.H., et al. [Study on the expression of microRNA-1825 in serum of pre-operative and post-operative patients with breast cancer]. Zhonghua Yu Fang Yi Xue Za Zhi. 2021; 55(5): 691-697.-DOI: https://doi.org/10.3760/cma.j.cn112150-20200921-01224.

Dong G., Wang X., Jia Y., et al. HAND2-AS1 Works as a ceRNA of miR-3118 to Suppress proliferation and migration in breast cancer by upregulating PHLPP2. Biomed Res Int. 2020; 2020: 8124570.-DOI: https://doi.org/10.1155/2020/8124570.

Carvalho T.M., Brasil G.O., Jucoski T.S., et al. MicroRNAs miR-142-5p, miR-150-5p, miR-320a-3p, and miR-4433b-5p in Serum and tissue: Potential biomarkers in sporadic breast cancer. Front Genet. 2022; 13: 865472.-DOI: https://doi.org/10.3389/fgene.2022.865472.

Satomi-Tsushita N., Shimomura A., Matsuzaki J., et al. Serum microRNA-based prediction of responsiveness to eribulin in metastatic breast cancer. PLoS One. 2019; 14(9): e0222024.-DOI: https://doi.org/10.1371/journal.pone.0222024.

Gao Y., Ma H., Gao C., et al. Tumor-promoting properties of miR-8084 in breast cancer through enhancing proliferation, suppressing apoptosis and inducing epithelial-mesenchymal transition. J Transl Med. 2018; 16(1): 38.-DOI: https://doi.org/10.1186/s12967-018-1419-5.

Honson D.D., Macfarlan T.S. A lncRNA-like role for LINE1s in development. Dev Cell. 2018; 46(2): 132-134.-DOI: https://doi.org/10.1016/j.devcel.2018.06.022.

Ma L., Zhang Y., Hu F. miR 28 5p inhibits the migration of breast cancer by regulating WSB2. Int J Mol Med. 2020; 46(4): 1562-1570.-DOI: https://doi.org/10.3892/ijmm.2020.4685.

Chen Q., Xu H., Zhu J., et al. LncRNA MCM3AP-AS1 promotes breast cancer progression via modulating miR-28-5p/CENPF axis. Biomed Pharmacother. 2020; 128: 110289.-DOI: https://doi.org/10.1016/j.biopha.2020.110289.

Zan X., Li W., Wang G., et al. Circ-CSNK1G1 promotes cell proliferation, migration, invasion and glycolysis metabolism during triple-negative breast cancer progression by modulating the miR-28-5p/LDHA pathway. Reprod Biol Endocrinol. 2022; 20(1): 138.-DOI: https://doi.org/10.1186/s12958-022-00998-z.

Poodineh J., Sirati-Sabet M., Rajabibazl M., Mohammadi-Yeganeh S. MiR-130a-3p blocks Wnt signaling cascade in the triple-negative breast cancer by targeting the key players at multiple points. Heliyon. 2020; 6(11): e05434.-DOI: https://doi.org/10.1016/j.heliyon.2020.e05434.

Xie D., Li S., Wu T. et al. MiR-181c suppresses triple-negative breast cancer tumorigenesis by targeting MAP4K4. Pathol Res Pract. 2022; 230: 153763.-DOI: https://doi.org/10.1016/j.prp.2022.153763.

Hao S., Tian W., Chen Y., et al. MicroRNA-374c-5p inhibits the development of breast cancer through TATA-box binding protein associated factor 7-mediated transcriptional regulation of DEP domain containing 1. J Cell Biochem. 2019; 120(9): 15360-15368.-DOI: https://doi.org/10.1002/jcb.28803.

Zhao L., Feng X., Song X., et al. miR-493-5p attenuates the invasiveness and tumorigenicity in human breast cancer by targeting FUT4. Oncol Rep. 2016; 36(2): 1007-15.-DOI: https://doi.org/10.3892/or.2016.4882.

Qiu X., Zhang Q., Deng Q., Li Q. Circular RNA hsa_circ_0012673 promotes breast cancer progression via miR-576-3p/SOX4 axis. Mol Biotechnol. 2023; 65(1): 61-71.-DOI: https://doi.org/10.1007/s12033-022-00524-x.

Sun L., Chen S., Wang T., Bi S. Hsa_circ_0008673 promotes breast cancer progression by MiR-578/GINS4 axis. Clin Breast Cancer. 2023; 23(3): 281-290.-DOI: https://doi.org/10.1016/j.clbc.2022.12.015.

Yuan D., Liu J., Sang W., Li Q. Comprehensive analysis of the role of SFXN family in breast cancer. Open Med (Wars). 2023; 18(1): 20230685.-DOI: https://doi.org/10.1515/med-2023-0685.

Zhang Z., Luo X., Xue X., et al. Engineered exosomes carrying miR-588 for treatment of triple negative breast cancer through remodeling the immunosuppressive microenvironment. Int J Nanomedicine. 2024; 19: 743-758.-DOI: https://doi.org/10.2147/IJN.S440619.

Choi S., An H.J., Yeo H.J., et al. MicroRNA 606 inhibits the growth and metastasis of triple negative breast cancer by targeting Stanniocalcin 1. Oncol Rep. 2024; 51(1): 2.-DOI: https://doi.org/10.3892/or.2023.8661.

Shi G., Li H., Chen Y., et al. CircSEPT9 promotes breast cancer progression by regulating PTBP3 expression via sponging miR-625-5p. Thorac Cancer. 2024; 15(10): 808-819.-DOI: https://doi.org/10.1111/1759-7714.15252.

Ren F., Rui X., Xiao X. Loss of miR-634 contributes to the formation FOXA1-positive triple negative breast cancer subtype. Discov Oncol. 2024; 15(1): 584.-DOI: https://doi.org/10.1007/s12672-024-01472-5.

Lee J.W., Guan W., Han S., et al. MicroRNA-708-3p mediates metastasis and chemoresistance through inhibition of epithelial-to-mesenchymal transition in breast cancer. Cancer Sci. 2018; 109(5): 1404-1413.-DOI: https://doi.org/10.1111/cas.13588.

Dong H.T., Liu Q., Zhao T., et al. Long Non-coding RNA LOXL1-AS1 Drives breast cancer invasion and metastasis by antagonizing miR-708-5p expression and activity. Mol Ther Nucleic Acids. 2020; 19: 696-705.-DOI: https://doi.org/10.1016/j.omtn.2019.12.016.

Ji C., Zhu L., Fang L. Hsa_circ_0000851 promotes PDK1/p-AKT-mediated cell proliferation and migration by regulating miR-1183 in triple-negative breast cancer. Cell Signal. 2023; 101: 110494.-DOI: https://doi.org/10.1016/j.cellsig.2022.110494.

Ding J., Wu W., Yang J., Wu M. Long non-coding RNA MIF-AS1 promotes breast cancer cell proliferation, migration and EMT process through regulating miR-1249-3p/HOXB8 axis. Pathol Res Pract. 2019; 215(7): 152376.-DOI: https://doi.org/10.1016/j.prp.2019.03.005

Yu T., Yu H.R., Sun J.Y., et al. miR-1271 inhibits ERα expression and confers letrozole resistance in breast cancer. Oncotarget. 2017; 8(63): 107134-107148.-DOI: https://doi.org/10.18632/oncotarget.22359.

Yu L., Zhang W., Wang P., et al. LncRNA SNHG11 aggravates cell proliferation and migration in triple-negative breast cancer via sponging miR-2355-5p and targeting CBX5. Exp Ther Med. 2021; 22(2): 892.-DOI: https://doi.org/10.3892/etm.2021.10324.

Luo X., Wang H. LINC00514 upregulates CCDC71L to promote cell proliferation, migration and invasion in triple-negative breast cancer by sponging miR-6504-5p and miR-3139. Cancer Cell Int. 2021; 21(1): 180.-DOI: https://doi.org/10.1186/s12935-021-01875-2.

Shin D., Yoo J.O., Jeong J.H., Han Y.H. MiR-5586-5p suppresses hypoxia-induced angiogenesis through multiple targeting of HIF-1α, HBEGF and ADAM17 in breast cancer. Anticancer Res. 2025; 45(2): 473-489.-DOI: https://doi.org/10.21873/anticanres.17437.

Wang D., Yang S., Lyu M., et al. Circular RNA HSDL2 promotes breast cancer progression via miR-7978 ZNF704 axis and regulating hippo signaling pathway. Breast Cancer Res. 2024; 26(1): 105.-DOI: https://doi.org/10.1186/s13058-024-01864-z.

Du H.Y., Liu B. MiR-1271 as a tumor suppressor in breast cancer proliferation and progression via targeting SPIN1. Eur Rev Med Pharmacol Sci. 2018; 22(9): 2697-2706.-DOI: https://doi.org/10.26355/eurrev_201805_14966.

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