Exosomal Proteasome Levels as a Potential Biomarker for Differentiating Mastopathy from Breast Cancer via Liquid Biopsy

Capa

Citar

Texto integral

Resumo

Introduction. Breast cancer (BC) remains the most prevalent malignancy among women worldwide. Limitations in mammography and ultrasound sensitivity, combined with the absence of reliable biomarkers for distinguishing benign from malignant breast lesions, frequently result in unnecessary biopsies and patient distress. Aim. To quantify 20S proteasome levels within blood-derived exosomes from patients with mastopathy and BC. Materials and Methods. The study included blood samples from clinically healthy women (n = 20), patients with diffuse dyshormonal breast dysplasia (n = 20), and BC patients (T1N0M0, n = 20). Exosomes were isolated from plasma and whole blood via ultracentrifugation and characterized using flow cytometry and nanoparticle tracking analysis. Following comprehensive exosomal protein profiling, 20S proteasome levels were quantified through Western blot analysis. levels were quantified through Western blot analysis. Results. 20S proteasomes within exosomes demonstrated neither chymotrypsin-like nor caspase-like enzymatic activity. However, their expression levels were significantly elevated in both plasma and whole blood exosomes from BC patients, with whole blood exosomes showing higher concentrations than plasma-derived exosomes. These findings suggest BC progression involves intercellular transfer of 20S proteasome subunits via blood exosomes from donor to recipient cells. Conclusion. Quantification of 20S proteasome levels in circulating exosomes shows potential for differentiating between benign and malignant breast diseases.

Sobre autores

S. Tamkovich

Federal State Budget Institution «Institute of Oncology and Neurosurgery, E.N. Meshalkin National Medical Research Center, Ministry of Healthcare of the Russian Federation; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences; Institute of Medicine and Medical Technologies, Novosibirsk State University

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0001-7774-943X
Código SPIN: 6462-3700
Scopus Author ID: 7801643574
Researcher ID: G-9790-2013
Novosibirsk, the Russian Federation

N. Yunusova

Cancer Research Institute, Tomsk National Research Medical Center

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0003-4595-4177
Código SPIN: 3513-1888
Scopus Author ID: 558006
Tomsk, the Russian Federation

D. Svarovsky

Cancer Research Institute, Tomsk National Research Medical Center

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0002-8985-009X
Código SPIN: 4131-8608
Scopus Author ID: 57417248900
Tomsk, the Russian Federation

T. Shtam

National Research Center “Kurchatov Institute”

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0003-0651-4785
Código SPIN: 3738-8187
Scopus Author ID: 95878
Gatchina, Leningrad Region, the Russian Federation

I. Kondakova

Cancer Research Institute, Tomsk National Research Medical Center

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0002-0947-8778
Código SPIN: 9338-4149
Scopus Author ID: 349081
Tomsk, the Russian Federation

A. Chernyshova

Federal State Budget Institution «Institute of Oncology and Neurosurgery, E.N. Meshalkin National Medical Research Center, Ministry of Healthcare of the Russian Federation; Institute of Medicine and Medical Technologies, Novosibirsk State University

Email: tamkovich_sn@meshalkin.ru
ORCID ID: 0000-0002-8194-2811
Código SPIN: 2522-7513
Scopus Author ID: 557924
Researcher ID: C-8608-2012
Novosibirsk, the Russian Federation

Bibliografia

  1. Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263. -DOI: https://doi.org/10.3322/caac.21834.-URL: https://pubmed.ncbi.nlm.nih.gov/38572751.
  2. Под ред. Каприна А.Д., Старинского В.В., Шахзадовой А.О. Злокачественные новообразования в России в 2020 г. (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2021; 252 (Ил.).-ISBN: 978-5-85502-268-1.-URL: https://oncology.ru/service/statistics/malignant_tumors/2021.pdf. [Ed. by Kaprin A.D., Starinsky V.V., Shakhzadova A.O. Malignant neoplasms in Russia in 2020 (incidence and mortality). Moscow: P.A. Herzen Moscow Research Institute of Oncology – the branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation. 2021; 252 (ill.).-ISBN: 978-5-85502-268-1.-URL: https://oncology.ru/service/statistics/malignant_tumors/2021.pdf (in Rus)].
  3. Игнатьева В.И., Грецова О.П., Стенина М.Б., et al. Социально-экономическое бремя рака молочной железы в РФ. Медицинские технологии. 2016; 4: 32-49.-EDN: XUXYQX.-URL: https://elibrary.ru/item.asp?id=28283208. [Ignatieva V.I., Gretsova O.P., Stenina M.B., et al. The socioeconomic burden of breast cancer in the Russian Federation. Medical Technologies. 2016; 4: 32-49.-EDN: XUXYQX.-URL: https://elibrary.ru/item.asp?id=28283208 (in Rus)].
  4. Winters S., Martin C., Murphy D., Shokar N.K. Breast cancer epidemiology, prevention, and screening. Prog Mol Biol Transl Sci. 2017; 151: 1-32.-DOI: https://doi.org/10.1016/bs.pmbts.2017.07.002.-URL: https://pubmed.ncbi.nlm.nih.gov/29096890.
  5. Alimirzaie S., Bagherzadeh M., Akbari M.R. Liquid biopsy in breast cancer: A comprehensive review. Clin Genet. 2019; 95: 643-660.-DOI: https://doi.org/10.1111/cge.13514.-URL: https://onlinelibrary.wiley.com/doi/10.1111/cge.13514.
  6. Cohen J.D., Li L., Wang Y., et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018; 359: 926-930.-DOI: https://doi.org/10.1126/science.aar3247.-URL: https://www.science.org/doi/10.1126/science.aar3247.
  7. Ye Q., Ling S., Zheng S., Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol Cancer. 2019; 18: 114.-DOI: https://doi.org/10.1186/s12943-019-1043-x.-URL: https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1043-x.
  8. Tay T.K.Y., Tan P.H. Liquid biopsy in breast cancer: A focused review. Arch Pathol Lab Med. 2020; 145: 678-686.-DOI: https://doi.org/10.5858/arpa.2019-0559-RA.-URL: https://meridian.allenpress.com/aplm/article/145/6/678/427493/Liquid-Biopsy-in-Breast-Cancer-A-Focused-Review.
  9. Aakel N., Mohammed R., Fathima A., et al. Role of exosome in solid cancer progression and its potential therapeutics in cancer treatment. Cancer Med. 2025; 14: e70941.-DOI: https://doi.org/10.1002/cam4.70941.-URL: https://onlinelibrary.wiley.com/doi/10.1002/cam4.70941.
  10. Tutanov O., Tamkovich S. The influence of proteins on fate and biological role of circulating DNA. Int J Mol Sci. 2022; 23: 13.-DOI: https://doi.org/10.3390/ijms23137224.-URL: https://www.mdpi.com/1422-0067/23/13/7224.
  11. Shefer A., Yalovaya A., Tamkovich S. Exosomes in breast cancer: involvement in tumor dissemination and prospects for liquid biopsy. Int J Mol Sci. 2022; 23: 8845.-DOI: https://doi.org/10.3390/ijms23168845.-URL: https://www.mdpi.com/1422-0067/23/16/8845.
  12. Whiteside T.L. The potential of tumor-derived exosomes for noninvasive cancer monitoring: an update. Expert Rev Mol Diagn. 2018; 18(12): 1029-1040.-DOI: https://doi.org/10.1080/14737159.2018.1544494.-URL: https://www.tandfonline.com/doi/full/10.1080/14737159.2018.1544494.
  13. Jia Y., Chen Y., Wang Q., et al. Exosome: emerging biomarker in breast cancer. Oncotarget. 2017; 8(25): 41717-41733.-DOI: https://doi.org/10.18632/oncotarget.16684.-URL: https://www.oncotarget.com/article/16684/text.
  14. Юнусова Н.В., Тугутова Е.А., Тамкович С.Н., Кондакова И.В. Роль тетраспанинов и протеаз экзосом в опухолевой прогрессии. Биомедицинская химия. 2018; 64(2): 123-133.-DOI: https://doi.org/10.18097/PBMC20186402123.-EDN: UPNJPO.-URL: https://elibrary.ru/item.asp?id=34959591. [Yunusova N.V., Tugutova E.A., Tamkovich S.N., Kondakova I.V. The role of tetraspanins and exosome proteases in tumor progression. Biomedical Chemistry. 2018; 64(2): 123-133.-DOI: https://doi.org/10.18097/PBMC20186402123.-EDN: UPNJPO.-URL: https://elibrary.ru/item.asp?id=34959591 (in Rus)].
  15. Mofers A., Pellegrini P., Linder S., D’Arcy P. Proteasome-associated deubiquitinases and cancer. Cancer Metastasis Rev. 2017; 36(4): 635-53.-DOI: https://doi.org/10.1007/s10555-017-9697-6.-URL: https://link.springer.com/article/10.1007/s10555-017-9697-6.
  16. Кондакова И.В., Юнусова Н.В., Спирина Л.В., et al. Связь активности внутриклеточных протеиназ с содержанием локомоторных белков в тканях первичных опухолей и метастазах при раке яичников. Биоорганическая химия. 2014; 40: 735-742.-DOI: https://doi.org/10.1134/s1068162014060089.-URL: https://link.springer.com/article/10.1134/S1068162014060089. [Kondakova I.V., Yunusova N.V., Spirina L.V., et al. Association between intracellular proteinase activities and the content of locomotor proteins in tissues of primary tumors and metastases of ovarian cancer. Russ J Bioorg Chem. 2014; 40: 735-742.-DOI: https://doi.org/10.1134/s1068162014060089.-URL: https://link.springer.com/article/10.1134/S1068162014060089 (in Rus)].
  17. Тамкович С.Н., Юнусова Н.В., Сомов А.К., et al. Сравнительный субпопуляционный анализ экзосом плазмы крови больных злокачественными новообразованиями. Биомедицинская химия. 2018; 64 (1): 110-114.-DOI: https://doi.org/10.18097/PBMC20186401110.-EDN: VDEYSP.-URL: https://elibrary.ru/item.asp?id=32469710. [Tamkovich S.N., Yunusova N.V., Somov A.K., et al. Comparative subpopulation analysis of exosomes in blood plasma of patients with malignant neoplasms. Biomedical Chemistry. 2018; 64 (1): 110-114.-DOI: https://doi.org/10.18097/PBMC20186401110.-EDN: VDEYSP.-URL: https://elibrary.ru/item.asp?id=32469710 (in Rus)].
  18. Konoshenko M., Sagaradze G., Orlova E., et al. Total blood exosomes in breast cancer: Potential role in crucial steps of tumorigenesis. Int J Mol Sci. 2020; 21(19): 7341.-DOI: https://doi.org/10.3390/ijms21197341.-URL: https://www.mdpi.com/1422-0067/21/19/7341.
  19. Tecalco-Cruz A.C., Ramírez-Jarquín J.O. Mechanisms that increase stability of estrogen receptor alpha in breast cancer. Clin Breast Cancer. 2017; 17: 1-10.-DOI: https://doi.org/10.1016/j.clbc.2016.07.015.-URL: https://www.sciencedirect.com/science/article/abs/pii/S1526820916302087?via%20%3Dihub.
  20. Sannino S., Brodsky J.L. Targeting protein quality control pathways in breast cancer. BMC Biol. 2017; 15: 109.-DOI: https://doi.org/10.1186/s12915-017-0449-4.-URL: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0449-4.
  21. Галь Э., Медьеши Г., Верецкеи Л. Электрофорез в разделении биологических макромолекул. М.: Мир. 1982; 446.-URL: https://rusneb.ru/catalog/000200_000018_rc_1115053. [Gal E., Medgyesi G., Veretsekai L. Electrophoresis in the separation of biological macromolecules. Moscow: Mir. 1982; 446.-URL: https://rusneb.ru/catalog/000200_000018_rc_1115053 (In Rus)].
  22. Шахзадова А.О., Старинский В.В., Лисичникова И.В. Состояние онкологической помощи населению России в 2022 году. Сибирский онкологический журнал. 2023; 22: 5-13.-EDN: PESHHL.-DOI: https://doi.org/10.21294/1814-4861-2023-22-5-5-13.-URL: https://elibrary.ru/item.asp?id=54888843. [Shakhzadova A.O., Starinsky V.V., Lisichnikova I.V. The State of cancer care in Russia in 2022. Siberian Journal of Oncology. 2023; 22: 5-13.-EDN: PESHHL.-DOI: https://doi.org/10.21294/1814-4861-2023-22-5-5-13.-URL: https://elibrary.ru/item.asp?id=54888843 (In Rus)].
  23. Tutanov O., Orlova E., Proskura K., et al. Proteomic analysis of blood exosomes from healthy females and breast cancer patients reveals an association between different exosomal bioactivity on non-tumorigenic epithelial cell and breast cancer cell migration in vitro. Biomolecules. 2020; 10(4): 495.-DOI: https://doi.org/10.3390/biom10040495.-URL: https://www.mdpi.com/2218-273X/10/4/495.
  24. Shashova E.E., Lyupina Y.V., Glushchenko S.A., et al. Proteasome functioning in breast cancer: Connection with clinical-pathological factors. PLoS ONE. 2014; 9(10): e109933.-DOI: https://doi.org/10.1371/journal.pone.0109933.-URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109933.
  25. Berges C., Haberstock H., Fuchs D., et al. Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. Immunology. 2008; 124: 234-246.-DOI: https://doi.org/10.1111/j.1365-2567.2007.02761.x.-URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2567.2007.02761.x.
  26. Moran E., Carbone F., Augusti V., et al. Proteasome inhibitors as immunosuppressants: Biological rationale and clinical experience. Semin Hematol. 2012; 49: 270-276.-DOI: https://doi.org/10.1053/j.seminhematol.2012.04.004.-URL: https://www.sciencedirect.com/science/article/abs/pii/S0037196312000273?via%20%3Dihub.
  27. Yunusova N.V., Zambalova E.A., Patysheva M.R., et al. Exosomal protease cargo as prognostic biomarker in colorectal cancer. Asian Pac J Cancer Prev. 2021; 22: 861-869.-DOI: https://doi.org/10.31557/APJCP.2021.22.3.861.-URL: https://journal.waocp.org/article_89525.html.

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Problems in Oncology, 2025

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).