Роль LINE-ретроэлементов в развитии рака молочной железы

Мустафин, Р. Н. (2026). Роль LINE-ретроэлементов в развитии рака молочной железы. VOPROSY ONKOLOGII, 72(1), OF–2368. https://doi.org/10.37469/0507-3758-2026-72-1-OF-2368

摘要

Рак молочной железы (РМЖ) является самым распространенным злокачественным новообразованием в мире. В 5 – 15% случаев болезнь является моногенной, обусловленной гетерозиготными герминальными мутациями в генах BRCA1, BRCA2, ATM, BARD1, CHEK2, RAD51D, RAD51C, PALB2. Большинство случаев РМЖ являются многофакторным заболеванием, ассоциированным с множеством SNP, многие из которых расположены в межгенных и интронных областях, где локализуются гены ретроэлементов и произошедших от них генов некодирующих РНК. Наиболее распространенными ретроэлементами в геноме человека являются LINE, активация которых при РМЖ определена в ряде научных публикаций. Описаны механизмы влияния LINE на канцерогенез РМЖ за счет активации геномной нестабильности, хромоанагенеза, образования онкогенов и инактивации онкосупрессоров. Можно предположить, что ассоциированные с РМЖ SNP оказывают свое влияние на развитие рака за счет активации и изменения свойств LINE и взаимодействующих с ними микроРНК. Анализ научной литературы подтверждает данное предположение: при РМЖ определено изменение экспрессии произошедших от ретроэлементов 17 онкогенных микроРНК, которые могут быть использованы в качестве мишеней для таргетной противоопухолевой терапии. Кроме того, описано 21 онкосупрессорных произошедших от LINE микроРНК, которые перспективны для лечения РМЖ. Описано также взаимодействие 8 произошедших от LINE микроРНК с длинными некодирующими РНК, в эволюции которых ключевую роль также играют ретроэлементы. Исследование этих данных может раскрыть новые механизмы патогенеза РМЖ с участием LINE, длинных некодирующих РНК и микроРНК.

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

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参考

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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