Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press60510.17650/2313-805X-2023-10-4-149-156SHORT REPORTКРАТКОЕ СООБЩЕНИЕThe effect of DNA methyltransferase 3A suppression in progression of the resistance phenotype in breast cancer cellsФеномен подавления ДНК-метилтрансферазы 3А при формировании резистентного фенотипа в клетках рака молочной железыhttps://orcid.org/0000-0002-6015-6619AndreevaO. E.АндрееваО. Е.
Russian Federation

Olga E. Andreeva.

24 Kashirskoe Shosse, Moscow 115522

Андреева Ольга Евгеньевна.

115522 Москва, Каширское шоссе, 24

o.andreeva@ronc.ruhttps://orcid.org/0000-0002-1264-7405SorokinD. V.СорокинД. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522; 23 Gagarin Prospekt, Nizhny Novgorod 603950

115522 Москва, Каширское шоссе, 24; 603022 Нижний Новгород, проспект Гагарина, 23

https://orcid.org/0000-0003-1615-3928VinokurovaS. V.ВинокуроваС. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-1490-6781ShchegolevYu. Yu.ЩеголевЮ.  Ю.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0503-6016ElkinaN. V.ЕлкинаН. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7405-0671KatarginA. N.КатаргинА. Н.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0050-7798FaskhutdinovR. S.ФасхутдиновР.  С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0809-3710SalnikovaD. I.Сальникова Д.  И.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522; Bld. 1, 11 Bol’shaya Pirogovskaya St., Moscow 119021

115522 Москва, Каширское шоссе, 24; Москва 119021, ул. Большая Пироговская, 11, стр. 1

https://orcid.org/0000-0002-2974-9555ScherbakovA. M.ЩербаковА. М.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522; 23 Gagarin Prospekt, Nizhny Novgorod 603950

115522 Москва, Каширское шоссе, 24; 603022 Нижний Новгород, проспект Гагарина, 23

https://orcid.org/0000-0002-5902-7633Krasil’nikovM. A.КрасильниковМ.  А.
Russian Federation

Mikhail A. Krasil’nikov.

24 Kashirskoe Shosse, Moscow 115522; 23 Gagarin Prospekt, Nizhny Novgorod 603950

Красильников Михаил Александрович.

115522 Москва, Каширское шоссе, 24; 603022 Нижний Новгород, проспект Гагарина, 23

krasilnikovm1@ya.ruN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииNational Research Lobachevsky State University of Nizhny NovgorodФГАОУ ВО «Национальный исследовательский Нижегородский государственный университет им. Н.И. Лобачевского»Gause Institute of New AntibioticsФГБНУ «Научно-исследовательский институт новых антибиотиков им. Г.Ф. Гаузе»151220231041491561411202314122023Copyright ©; 2023, Andreeva O.E., Sorokin D.V., Vinokurova S.V., Shchegolev Y.Y., Elkina N.V., Katargin A.N., Faskhutdinov R.S., Salnikova D.I., Scherbakov A.M., Krasil’nikov M.A.Copyright ©; 2023, Андреева О.Е., Сорокин Д.В., Винокурова С.В., Щеголев Ю.Ю., Елкина Н.В., Катаргин А.Н., Фасхутдинов Р.С., Сальникова  .И., Щербаков А.М., Красильников М.А.2023Andreeva O.E., Sorokin D.V., Vinokurova S.V., Shchegolev Y.Y., Elkina N.V., Katargin A.N., Faskhutdinov R.S., Salnikova D.I., Scherbakov A.M., Krasil’nikov M.A.Андреева О.Е., Сорокин Д.В., Винокурова С.В., Щеголев Ю.Ю., Елкина Н.В., Катаргин А.Н., Фасхутдинов Р.С., Сальникова  .И., Щербаков А.М., Красильников М.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/605

Introduction. Rearrangement of molecular pathways and activation of bypass signaling determine the progression of tumor cell resistance to various drugs. Study of the common features of resistant formation mechanisms is essential for breast and other cancer beneficial treatments.

Materials and methods. The present work was performed on estrogen receptor α ERα-positive (ERα – estrogen receptor α) McF-7 breast cancer cells, established sublines resistant to the mTOR inhibitor rapamycin or antiestrogen tamoxifen, and ERα-negative MDA-MB-231 breast cancer cells. Methods used include MTT test, transient transfection, immunoblotting, real-time polymerase chain reaction and methylation analysis by bisulfite pyrosequencing.

Results. We have shown that the resistance of breast cancer cells to targeted and hormonal drugs is associated with the suppression of DNA methyltransferase 3A (DNMT3A) and respective changes in DNA methylation; DNMT3A knockdown results in the partial resistance to both drugs demonstrating the pivotal role of DNMT3A suppression in the progression of cell resistance.

Conclusion. Totally, the results obtained highlight the possible mechanism of tumor cell resistance to targeting/hormonal drugs based on the deregulation of DNMTs expression and demonstrate  direct connection between DNMT3A suppression and resistance progression.

Введение. Переключение сигнальных путей и активация параллельных сигнальных каскадов относятся к ключевым факторам, определяющим развитие резистентности опухолевых клеток, и изучение механизмов подобной реаранжировки является одной из актуальных задач современной онкологии.

Материалы и методы. Настоящая работа выполнена на ERα-положительных  (ERα – эстрогеновый рецептор α) клетках рака молочной железы MCF-7 и полученных из них сублиниях, устойчивых к ингибитору mTOR рапамицину или антиэстрогену тамоксифену, а также на ERα-отрицательных клетках рака молочной железы MDA-MB-231. Используемые методы включают тест МТТ, транзиторную трансфекцию, иммуноблоттинг, полимеразную цепную реакцию в реальном времени и анализ метилирования с помощью бисульфитного пиросеквенирования.

Результаты. Мы показали, что резистентность клеток рака молочной железы к таргетным и гормональным препаратам связана с подавлением ДНК-метилтрансферазы 3А (DNMT3A) и соответствующими изменениями в метилировании ДНК. Нокдаун DNMT3A приводит к частичной резистентности к обоим препаратам, что демонстрирует ключевую роль подавления DNMT3A в развитии резистентности опухолевых клеток.

Заключение. В целом, полученные результаты свидетельствуют о возможном механизме формирования устойчивости опухолевых клеток к таргетным/гормональным препаратам, основанном на дерегуляции экспрессии DNMT, и демонстрируют прямую связь между подавлением DNMT3A и развитием резистентности.

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