oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2024-23-3-73-85oncotomsk-3115Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESАнтитела и анти-антитела, специфичные к эстрадиолу и прогестерону, и пролиферативная активность опухоли у больных раком молочной железыAntibodies and anti-antibodies specific to estradiol and progesterone and tumor proliferation in breast cancer patientshttps://orcid.org/0000-0002-8560-6719ГлушковА. Н.GlushkovA. N.

Глушков Андрей Николаевич, доктор медицинских наук, профессор, главный научный сотрудник лаборатории иммуногенетики

Author ID (Scopus): 7006323832. Researcher ID (WOS): Q-5985-2016 

 Россия, 650065, г. Кемерово, пр-т Ленинградский, 10 

Andrey N. Glushkov, MD, Professor, Chief Researcher, Immunogenetics Laboratory

Author ID (Scopus): 7006323832. Researcher ID (WOS): Q-5985-2016

10, Leningradsky Ave., Kemerovo, 650065, Russia

https://orcid.org/0000-0002-9368-2340ПоленокЕ. Г.PolenokE. G.

 Поленок Елена Геннадьевна, кандидат фармацевтических наук, ведущий научный сотрудник лаборатории иммунохимии

Author ID (Scopus): 6506567994. Researcher ID (WOS): Q-5381-2016 

 Россия, 650065, г. Кемерово, пр-т Ленинградский, 10 

Elena G. Polenok, PhD, Leading Researcher, Immunochemistry Laboratory,  

Author ID (Scopus): 6506567994. Researcher ID (WOS): Q-5381-2016 

10, Leningradsky Ave., Kemerovo, 650065, Russia

egpolenok@mail.ruhttps://orcid.org/0000-0001-5870-7584ГордееваЛ. А.GordeevaL. A.

Гордеева Людмила Александровна, кандидат биологических наук, ведущий научный сотрудник лаборатории иммуногенетики

Author ID (Scopus): 14052058500. Researcher ID (WOS): R-2781-2016

Россия, 650065, г. Кемерово, пр-т Ленинградский, 10 

Lyudmila A. Gordeeva, PhD, Leading Researcher, Immunogenetics Laboratory,

Author ID (Scopus): 14052058500. Researcher ID (WOS): R-2781-2016 

10, Leningradsky Ave., Kemerovo, 650065, Russia

https://orcid.org/0000-0002-4649-5892БайрамовП. В.BayramovP. V.

Байрамов Павел Валерьевич, заведующий патологоанатомическим отделением 

 Россия, 650036, г. Кемерово, ул. Волгоградская, 35 

Pavel V. Bayramov, Head of the Pathological Department

35, Volgogradskaya St., Kemerovo, 650036, Russia

https://orcid.org/0000-0003-3860-825XВержбицкаяН. Е.VerzhbitskayaN. E.

Вержбицкая Наталья Евгеньевна, кандидат медицинских наук, врач-патологоанатом

Россия, 650036, г. Кемерово, ул. Волгоградская, 35 

 Natalia E. Verzhbitskaya, MD, PhD, Pathologist, Pathological Department 

35, Volgogradskaya St., Kemerovo, 650036, Russia

https://orcid.org/0000-0003-0802-9759АнтоновА. В.AntonovA. V.

Антонов Александр Витальевич, заведующий отделением опухолей молочной железы

Россия, 650036, г. Кемерово, ул. Волгоградская, 35 

 Alexander V. Antonov, Head of the Department of Breast Cancer 

35, Volgogradskaya St., Kemerovo, 650036, Russia

https://orcid.org/0000-0002-5526-2687КолпинскийГ. И.KolpinskyG. I.

Колпинский Глеб Иванович, доктор медицинских наук, профессор кафедры лучевой диагностики и лучевой терапии с курсом онкологии; главный врач

Author ID (Scopus): 56677706300 

Россия, 650066, г. Кемерово, пр-т Октябрьский, 53/1 

Россия, 650000, г. Кемерово, ул. Красная, 6

Gleb I. Kolpinsky, MD, Professor, Department of Radiation Diagnostics and Radiation Therapy with a Course in Oncology; Chief Physician

Author ID (Scopus): 56677706300 

53/1, Oktyabrsky Ave., Kemerovo, 650066, Russia

6, Krasnaya St., Kemerovo, 650000, Russia

https://orcid.org/0000-0003-0053-1752КостянкоМ. В.KostyankoM. V.

Костянко Михаил Владимирович, ведущий инженер кафедры фундаментальной и прикладной химии, Институт фундаментальных наук

Author ID (Scopus): 6507008191

Россия, 650000, г. Кемерово, ул. Красная, 6

 Mikhail V. Kostyanko, Leading Engineer, Department of Fundamental and Applied Chemistry

Author ID (Scopus): 6507008191 

6, Krasnaya St., Kemerovo, 650000, Russia

Институт экологии человека, ФГБНУ «Федеральный исследовательский центр угля и углехимии СО РАН»РоссияInstitute of Human Ecology, Federal Research Center for Coal and Coal Chemistry SB RASRussian FederationГБУЗ «Кузбасский клинический онкологический диспансер им. М.С. Раппопорта»РоссияKuzbass Clinical Oncology Dispensary named after. M.S. Rappoport Russian FederationГАУЗ «Клинический консультативно-диагностический центр им. И.А. Колпинского»; ФГБОУ ВО «Кемеровский государственный университет»РоссияKemerovo State University; Clinical Consultative and Diagnostic Center named after. I.A. KolpinskyRussian FederationФГБОУ ВО «Кемеровский государственный университет»РоссияInstitute of Fundamental Sciences, Kemerovo State UniversityRussian Federation2024030720242337385Copyright © Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Байрамов П.В., Вержбицкая Н.Е., Антонов А.В., Колпинский Г.И., Костянко М.В., 20242024Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Байрамов П.В., Вержбицкая Н.Е., Антонов А.В., Колпинский Г.И., Костянко М.В.Glushkov A.N., Polenok E.G., Gordeeva L.A., Bayramov P.V., Verzhbitskaya N.E., Antonov A.V., Kolpinsky G.I., Kostyanko M.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/3115

Цель исследования – выявление взаимосвязей уровней антител, специфичных к эстрадиолу и прогестерону (IgA1-E2 и IgA1-Pg), и соответствующих антиидиотипических антител (IgG2-E2 и IgG2-Pg) в сыворотке крови у больных раком молочной железы (РМЖ) с содержанием в опухоли Ki67-положительных клеток. Материал и методы. Содержание антител в сыворотке крови больных РМЖ I стадии (n=522) и II –IV стадий (n=578) исследовали с помощью неконкурентного иммуноферментного анализа, используя в качестве адсорбированных антигенов конъюгаты E2 и Pg c белком-носителем и моноклональные антитела против E2 и Pg соответственно. Уровень Ki67 в опухолях исследовали с помощью иммуногистохимического метода. Статистический анализ результатов выполняли, используя программу Statistica 8.0. Результаты. У больных РМЖ I стадии искомых взаимосвязей не выявлено. У больных РМЖ II –IV стадий при совместном повышении уровней IgA1-E2 и IgA1-Pg опухоли с высоким содержанием Ki67+ клеток (>20,0 %) встречались чаще, чем у больных с их низкими уровнями (68,8 vs 58,0 %, р=0,02). Напротив, при одновременном повышении уровней IgG2-E2 и IgG2-Pg опухоли с Ki67>20,0 % встречались реже, чем у больных с их высокими уровнями (49,6 vs 65,2 %, р=0,002). У больных с одновременно высокими уровнями IgA1-E2 и IgA1-Pg в комбинации с одновременно низкими уровнями IgG2-E2 и IgG2-Pg опухоли с Ki67>20,0 % обнаруживали в 42,9 % случаев при I стадии и в 77,1 % при II –IV стадиях (p<0,001). У больных РМЖ с обратным соотношением исследуемых антител эта разница практически отсутствовала (46,7 и 48,2 % соответственно, р=0,985). Заключение. Антитела против E2 и Pg синергически стимулируют, а соответствующие антиидиотипические антитела синергически угнетают пролиферативную активность опухоли у больных РМЖ. Иммуноанализ антител и анти-антител к стероидным гормонам рекомендуется для исследования механизмов прогрессирования других гормонозависимых новообразований у человека.

The study was aimed to determine the interrelations between levels of serum antibodies specific to estradiol and progesterone (IgA1-E2 and IgA1-Pg) and corresponding antiidiotypic antibodies (IgG2-E2 and IgG2-Pg) and tumor Ki67 positive cells in breast cancer patients (BCP). Material and Methods. The content of these antibodies in the blood serum of BCP (522 at the I stage and 578 at the II –IV stages) was studied using non-competitive enzyme immunoassay. Ki67 was determined using immunohistochemical method. Statistical analysis of the results was performed using the Statistica 8.0 software. Results. There were no revealed the desired associations in BCP I stage. Tumors with high levels of Ki67 positive cells (>20,0 %) were found more often in BCP II –IV stages with high serum levels of IgA1-E2 together with IgA1-Pg than in BCP with low levels of these antibodies (68.8 vs 58.0 %, р=0.02). In contrast, tumors with Ki67>20,0 % were revealed less often in BCP with high levels of IgG2-E2 together with IgG2-Pg (49.6 vs 65.2 %, р=0.002). Tumors with high levels of Ki67 positive cells were revealed in 42.9 % BCP I stage and in 77.1 % BCP II –IV stages with high serum levels of IgA1-E2 and IgA1-Pg in combination with low serum levels of IgG2-E2 and IgG2-Pg (p<0.001). There were no such differences between BCP I and II -IV stages with low levels of IgA1-E2 and IgA1-Pg in combination with high levels of IgG2-E2 and IgG2-Pg (46.7 vs 48.2 %, accordingly, р=0.985). Conclusion. Antibodies against E2 and Pg synergistically promoted, but corresponding antiidiotypic antibodies synergistically inhibited the tumors proliferation in BCP. Immunoassay of antibodies and anti-antibodies to steroids is recommended for research of human hormone-dependent neoplasms progression.

антителаэстрадиолпрогестеронKi67рак молочной железыantibodiesestradiolprogesteroneKi67breast cancerРабота выполнена по государственному заданию (проект АААА-А21-121011590009-9) Министерства науки и образования Российской Федерации.The work was carried out according to the state assignment (project AAAA-A21-121011590009-9) of the Ministry of Science and Education of the Russia.ReferencesМерабишвили В.М., Семиглазов В.Ф., Комяхов А.В., Семиглазова Т.Ю., Криворотько П.В., Беляев А.М. Состояние онкологической помощи в России: рак молочной железы. Эпидемиология и выживаемость больных. Влияние эпидемии бета-варианта коронавируса SARS-CoV-2 (клинико-популяционное исследование). Опухоли женской репродуктивной системы. 2023; 19(3): 16–24. doi: 10.17650/1994-4098-2023-19-3-16-24.Merabishvili V.M., Semiglazov V.F., Komiakhov A.V., Semiglazova T.Yu., Krivorotko P.V., Belyaev А.M. The state of cancer care in Russia: breast cancer. Epidemiology and survival of patients. The impact of the SARS-CoV-2-beta-coronavirus epidemic (clinical and population study). Tumors of Female Reproductive System. 2023; 19(3): 16–24. (in Russian). doi: 10.17650/1994-4098-2023-19-3-16-24.Nielsen T.O., Leung S.C.Y., Rimm D.L., Dodson A., Acs B., Badve S., Denkert C., Ellis M.J., Fineberg S., Flowers M., Kreipe H.H., Laenkholm A.V., Pan H., Penault-Llorca F.M., Polley M.Y., Salgado R., Smith I.E., Sugie T., Bartlett J.M.S., McShane L.M., Dowsett M., Hayes D.F. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2021; 113(7): 808–19. doi: 10.1093/jnci/djaa201.Nielsen T.O., Leung S.C.Y., Rimm D.L., Dodson A., Acs B., Badve S., Denkert C., Ellis M.J., Fineberg S., Flowers M., Kreipe H.H., Laenkholm A.V., Pan H., Penault-Llorca F.M., Polley M.Y., Salgado R., Smith I.E., Sugie T., Bartlett J.M.S., McShane L.M., Dowsett M., Hayes D.F. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2021; 113(7): 808–19. doi: 10.1093/jnci/djaa201.Hacking S.M., Wang Y. Practical Issues of Ki67 Evaluation in Breast Cancer Clinical Practice. J Clin Transl Pathol. 2022; 2(2): 53–6. doi: 10.14218/jctp.2022.00012.Hacking S.M., Wang Y. Practical Issues of Ki67 Evaluation in Breast Cancer Clinical Practice. J Clin Transl Pathol. 2022; 2(2): 53–6. doi: 10.14218/jctp.2022.00012.Fortunati N., Catalano M.G., Boccuzzi G., Frairia R. Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer. Mol Cell Endocrinol. 2010; 316(1): 86–92. doi: 10.1016/j.mce.2009.09.012.Fortunati N., Catalano M.G., Boccuzzi G., Frairia R. Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer. Mol Cell Endocrinol. 2010; 316(1): 86–92. doi: 10.1016/j.mce.2009.09.012.Dimou N.L., Papadimitriou N., Gill D., Christakoudi S., Murphy N., Gunter M.J., Travis R.C., Key T.J., Fortner R.T., Haycock P.C., Lewis S.J., Muir K., Martin R.M., Tsilidis K.K. Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study. Int J Epidemiol. 2019; 48(3): 807–16. doi: 10.1093/ije/dyz107.Dimou N.L., Papadimitriou N., Gill D., Christakoudi S., Murphy N., Gunter M.J., Travis R.C., Key T.J., Fortner R.T., Haycock P.C., Lewis S.J., Muir K., Martin R.M., Tsilidis K.K. Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study. Int J Epidemiol. 2019; 48(3): 807–16. doi: 10.1093/ije/dyz107.Elsaesser F. Effects of active immunization against oestradiol-17 beta, testosterone or progesterone on receptivity in the female rabbit and evaluation of specificity. J Reprod Fertil. 1980; 58(1): 213–8. doi: 10.1530/jrf.0.0580213.Elsaesser F. Effects of active immunization against oestradiol-17 beta, testosterone or progesterone on receptivity in the female rabbit and evaluation of specificity. J Reprod Fertil. 1980; 58(1): 213–8. doi: 10.1530/jrf.0.0580213.Rosenberg M., Amir D., Folman Y. The effect of active immunization against progesterone on plasma concentrations of total and free progesterone, estradiol-17beta and LH in the cyclic ewe. Theriogenology. 1987; 28(4): 417–26. doi: 10.1016/0093-691x(87)90246-9.Rosenberg M., Amir D., Folman Y. The effect of active immunization against progesterone on plasma concentrations of total and free progesterone, estradiol-17beta and LH in the cyclic ewe. Theriogenology. 1987; 28(4): 417–26. doi: 10.1016/0093-691x(87)90246-9.Bochskanl R., Thie M., Kirchner C. Active immunization of rabbits against progesterone: increase in hormone levels, and changes in metabolic clearance rates and in genital tract tissues. J Steroid Biochem. 1989; 33(3): 349–55. doi: 10.1016/0022-4731(89)90323-3.Bochskanl R., Thie M., Kirchner C. Active immunization of rabbits against progesterone: increase in hormone levels, and changes in metabolic clearance rates and in genital tract tissues. J Steroid Biochem. 1989; 33(3): 349–55. doi: 10.1016/0022-4731(89)90323-3.Caldwell B.V., Tillson S.A., Esber H., Thorneycroft I.H. Survival of tumours after immunization against oestrogens. Nature. 1971; 231(5298): 118–9. doi: 10.1038/231118a0.Caldwell B.V., Tillson S.A., Esber H., Thorneycroft I.H. Survival of tumours after immunization against oestrogens. Nature. 1971; 231(5298): 118–9. doi: 10.1038/231118a0.Аверьянов А.В., Антонов А.В., Животовский А.С., Костянко М.В., Вафин И.А., Колпинский Г.И. Антитела класса G, специфичные к бензо[а]пирену, эстрадиолу и прогестерону у женщин с колоректальным раком и раком молочной железы. Сибирский онкологический журнал. 2022; 21(5): 52–8. doi: 10.21294/1814-4861-2022-21-5-52-58.Averianov A.V., Antonov A.V., Zhivotovsky A.S., Kostyanko M.V., Vafin I.A., Kolpinskiy G.I. Class G antibodies specific for benzo[a]pyrene, estradiol and progesterone in women with colorectal cancer. Siberian Journal of Oncology. 2022; 21(5): 52–8. (in Russian). doi: 10.21294/1814-4861-2022-21-5-52-58.Norfleet A.M., Clarke C.H., Gametchu B., Watson C.S. Antibodies to the estrogen receptor-alpha modulate rapid prolactin release from rat pituitary tumor cells through plasma membrane estrogen receptors. FASEB J. 2000; 14(1): 157–65. doi: 10.1096/fasebj.14.1.157.Norfleet A.M., Clarke C.H., Gametchu B., Watson C.S. Antibodies to the estrogen receptor-alpha modulate rapid prolactin release from rat pituitary tumor cells through plasma membrane estrogen receptors. FASEB J. 2000; 14(1): 157–65. doi: 10.1096/fasebj.14.1.157.Luconi M., Francavilla F., Porazzi I., Macerola B., Forti G., Baldi E. Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens. Steroids. 2004; 69(8–9): 553–9. doi: 10.1016/j.steroids.2004.05.013.Luconi M., Francavilla F., Porazzi I., Macerola B., Forti G., Baldi E. Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens. Steroids. 2004; 69(8–9): 553–9. doi: 10.1016/j.steroids.2004.05.013.Modi D.N., Shah C., Puri C.P. Non-genomic membrane progesterone receptors on human spermatozoa. Soc Reprod Fertil Suppl. 2007; 63: 515–29.Modi D.N., Shah C., Puri C.P. Non-genomic membrane progesterone receptors on human spermatozoa. Soc Reprod Fertil Suppl. 2007; 63: 515–29.Schwartz N., Verma A., Bivens C.B., Schwartz Z., Boyan B.D. Rapid steroid hormone actions via membrane receptors. Biochim Biophys Acta. 2016; 1863(9): 2289–98. doi: 10.1016/j.bbamcr.2016.06.004.Schwartz N., Verma A., Bivens C.B., Schwartz Z., Boyan B.D. Rapid steroid hormone actions via membrane receptors. Biochim Biophys Acta. 2016; 1863(9): 2289–98. doi: 10.1016/j.bbamcr.2016.06.004.Borkowski A., Gyling M., Muquardt C., Body J.J., Leslercq G. Estrogen-like activity of a subpopulation of natural antiestrogen receptor autoantibodies in man. Endocrinology. 1991; 128(6): 3283–92. doi: 10.1210/endo-128-6-3283.Borkowski A., Gyling M., Muquardt C., Body J.J., Leslercq G. Estrogen-like activity of a subpopulation of natural antiestrogen receptor autoantibodies in man. Endocrinology. 1991; 128(6): 3283–92. doi: 10.1210/endo-128-6-3283.Tassignon J., Haeseleer F., Borkowski A. Natural antiestrogen receptor autoantibodies in man with estrogenic activity in mammary carcinoma cell culture: study of their mechanism of action; evidence for involvement of estrogen-like epitopes. J Clin Endocrinol Metab. 1997; 82(10): 3464–70. doi: 10.1210/jcem.82.10.4313.Tassignon J., Haeseleer F., Borkowski A. Natural antiestrogen receptor autoantibodies in man with estrogenic activity in mammary carcinoma cell culture: study of their mechanism of action; evidence for involvement of estrogen-like epitopes. J Clin Endocrinol Metab. 1997; 82(10): 3464–70. doi: 10.1210/jcem.82.10.4313.Chaudhri R.A., Schwartz N., Elbaradie K., Schwartz Z., Boyan B.D. Role of ERα 36 in membrane-associated signaling by estrogen. Steroids. 2014; 81: 74–80. doi: 10.1016/j.steroids.2013.10.020.Chaudhri R.A., Schwartz N., Elbaradie K., Schwartz Z., Boyan B.D. Role of ERα 36 in membrane-associated signaling by estrogen. Steroids. 2014; 81: 74–80. doi: 10.1016/j.steroids.2013.10.020.Ortona E., Pierdominici M., Berstein L. Autoantibodies to estrogen receptors and their involvement in autoimmune diseases and cancer. J Steroid Biochem Mol Biol. 2014; 144: 260–7. doi: 10.1016/j.jsbmb.2014.07.004.Ortona E., Pierdominici M., Berstein L. Autoantibodies to estrogen receptors and their involvement in autoimmune diseases and cancer. J Steroid Biochem Mol Biol. 2014; 144: 260–7. doi: 10.1016/j.jsbmb.2014.07.004.Sömjen D., Amir-Zaltsman Y., Mor G., Gayer B., Lichter S., Barnard G., Kohen F. Anti-idiotypic antibody as an oestrogen mimetic in vivo: stimulation of creatin kinase specific activity in rat animal models. J Endocrinol. 1996; 149(2): 305–12. doi: 10.1677/joe.0.1490305.Sömjen D., Amir-Zaltsman Y., Mor G., Gayer B., Lichter S., Barnard G., Kohen F. Anti-idiotypic antibody as an oestrogen mimetic in vivo: stimulation of creatin kinase specific activity in rat animal models. J Endocrinol. 1996; 149(2): 305–12. doi: 10.1677/joe.0.1490305.Sömjen D., Kohen F., Lieberherr M. Nongenomic effects of an anti-idiotypic antibody as an estrogen mimetic in female human and rat osteoblasts. J Cell Biochem. 1997; 65(1): 53–66. doi: 10.1002/(SICI)1097-4644(199704)65:1<53::AID-JCB6>3.0.CO;2-Y.Sömjen D., Kohen F., Lieberherr M. Nongenomic effects of an anti-idiotypic antibody as an estrogen mimetic in female human and rat osteoblasts. J Cell Biochem. 1997; 65(1): 53–66. doi: 10.1002/(SICI)1097-4644(199704)65:1<53::AID-JCB6>3.0.CO;2-Y.Maselli A., Capoccia S., Pugliese P., Raggi C., Cirulli F., Fabi A., Malorni W., Pierdominici M., Ortona E. Autoantibodies specific to estrogen receptor alpha act as estrogen agonists and their levels correlate with breast cancer cell proliferation. Oncoimmunology. 2015; 5(2). doi: 10.1080/2162402X.2015.1074375.Maselli A., Capoccia S., Pugliese P., Raggi C., Cirulli F., Fabi A., Malorni W., Pierdominici M., Ortona E. Autoantibodies specific to estrogen receptor alpha act as estrogen agonists and their levels correlate with breast cancer cell proliferation. Oncoimmunology. 2015; 5(2). doi: 10.1080/2162402X.2015.1074375.Поленок Е.Г., Гордеева Л.А., Мун С.А., Костянко М.В., Антонов А.В., Вержбицкая Н.Е., Байрамов П.В., Колпинский Г.И., Вафин И.А., Глушков А.Н. Кооперативное участие идиотипических и антиидиотипических антител в стероид-зависимом химическом канцерогенезе. Российский иммунологический журнал. 2023; 26(1): 27–40. doi: 10.46235/1028-7221-1177-COI.Polenok E.G., Gordeeva L.A., Mun S.A., Kostyanko M.V., Antonov A.V., Verzhbitskaya N.E., Bairamov P.V., Kolpinskiy G.I., Vafin I.A., Glushkov A.N. Cooperation of idiotypic and anti-idiotypic antibodies at the steroid-depended chemical carcinogenesis. Russian Journal of Immunology. 2023; 26(1): 27–40. (in Russian). doi: 10.46235/1028-7221-1177-COI.Jerne N.K. Idiotypic networks and other preconceived ideas. Immunol Rev. 1984; 79: 5–24. doi: 10.1111/j.1600-065x.1984.tb00484.x.Jerne N.K. Idiotypic networks and other preconceived ideas. Immunol Rev. 1984; 79: 5–24. doi: 10.1111/j.1600-065x.1984.tb00484.x.Глушков А.Н., Поленок Е.Г., Мун С.А., Гордеева Л.А., Костянко М.В., Антонов А.В., Вержбицкая Н.Е., Вафин И.А. Индивидуальный иммунологический фенотип и риск рака молочной железы у женщин в постменопаузе. Российский иммунологический журнал. 2019; 13(1): 44–52. doi: 10.31857/S102872210005019-5.Glushkov A.N., Polenok E.G., Mun S.A., Gordeeva L.A., Kostyanko M.V., Antonov A.V., Verzhbitskaya N.E., Vafin I.A. Personal immunological phenotype and breast cancer risk in postmenopausal women. Russian Journal of Immunology. 2019; 13(1): 44–52. (in Russian). doi: 10.31857/S102872210005019-5.Greiner M., Pfeiffer D., Smith R.D. Principles and practical application of the receiver operating characteristic analysis for diagnostic test. Prev Vet Med. 2000; 45(1–2): 23–41. doi: 10.1016/s0167-5877(00)00115-x.Greiner M., Pfeiffer D., Smith R.D. Principles and practical application of the receiver operating characteristic analysis for diagnostic test. Prev Vet Med. 2000; 45(1–2): 23–41. doi: 10.1016/s0167-5877(00)00115-x.Pruthi S., Yang L., Sandhu N.P., Ingle J.N., Beseler C.L., Suman V.J., Cavalieri E.L., Rogan E.G. Evaluation of serum estrogen-DNA adducts as potential biomarkers for breast cancer risk. J. Steroid Biochem. Mol Biol. 2012; 132(1–2): 73–9. doi: 10.1016/j.jsbmb.2012.02.002.Pruthi S., Yang L., Sandhu N.P., Ingle J.N., Beseler C.L., Suman V.J., Cavalieri E.L., Rogan E.G. Evaluation of serum estrogen-DNA adducts as potential biomarkers for breast cancer risk. J. Steroid Biochem. Mol Biol. 2012; 132(1–2): 73–9. doi: 10.1016/j.jsbmb.2012.02.002.Yang L., Zahid M., Liao Y., Rogan E.G., Cavalieri E.L., Davidson N.E., Yager J.D., Visvanathan K., Groopman J.D., Kensler T.W. Reduced formation of depurinating estrogen–DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells. Carcinogenesis. 2013; 34(11): 2587–92. doi: 10.1093/carcin/bgt246.Yang L., Zahid M., Liao Y., Rogan E.G., Cavalieri E.L., Davidson N.E., Yager J.D., Visvanathan K., Groopman J.D., Kensler T.W. Reduced formation of depurinating estrogen–DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells. Carcinogenesis. 2013; 34(11): 2587–92. doi: 10.1093/carcin/bgt246.Yager J.D. Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention – A review. Steroids. 2015; 99: 56–60. doi: 10.1016/j.steroids.2014.08.006.Yager J.D. Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention – A review. Steroids. 2015; 99: 56–60. doi: 10.1016/j.steroids.2014.08.006.Alluri P.G., Speers C., Chinnaiyan A.M. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014; 16(6): 494. doi: 10.1186/s13058-014-0494-7.Alluri P.G., Speers C., Chinnaiyan A.M. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014; 16(6): 494. doi: 10.1186/s13058-014-0494-7.Harrod A., Lai C.-F., Goldsbrough I., Simmons G.M., Oppermans N., Santos D.B., Győrffy B., Allsopp R.C., Toghill B.J., Balachandran K., Lawson M., Morrow C.J., Surakala M., Carnevalli L.S., Zhang P., Guttery D.S., Shaw J.A., Coombes R.C., Buluwela L., Ali S. Genome engineering for estrogen receptor mutations reveals differential responses to antiestrogens and new prognostic gene signatures for breast cancer. Oncogene. 2022; 41(44): 4905–15. doi: 10.1038/s41388-022-02483-8.Harrod A., Lai C.-F., Goldsbrough I., Simmons G.M., Oppermans N., Santos D.B., Győrffy B., Allsopp R.C., Toghill B.J., Balachandran K., Lawson M., Morrow C.J., Surakala M., Carnevalli L.S., Zhang P., Guttery D.S., Shaw J.A., Coombes R.C., Buluwela L., Ali S. Genome engineering for estrogen receptor mutations reveals differential responses to antiestrogens and new prognostic gene signatures for breast cancer. Oncogene. 2022; 41(44): 4905–15. doi: 10.1038/s41388-022-02483-8.Leclercq G. Natural anti-estrogen receptor alpha antibodies able to induce estrogenic responses in breast cancer cells: hypotheses concerning their mechanisms of action and emergence. Int J Mol Sci. 2018; 19(2): 411. doi: 10.3390/ijms19020411.Leclercq G. Natural anti-estrogen receptor alpha antibodies able to induce estrogenic responses in breast cancer cells: hypotheses concerning their mechanisms of action and emergence. Int J Mol Sci. 2018; 19(2): 411. doi: 10.3390/ijms19020411.

The authors declare that there are no conflicts of interest present.