Antiidiotypic antibodies to estradiol and gene polymorphisms of α and β estrogenic receptors in breast cancer patients

Markers for identification of ER+/PR breast cancer (BC) risks and conversion of ER+/ER+ to ER-/PR- tumors are necessary for effective prevention and therapy of BC by the selective ER – modificators. Purpose – To reveal the proposed associations of gene polymorphisms of   ESR1 and ESR2 and antiidiotypic antibodies to estradiol (IgG2-E2) with ER+/PR+ BC risk and conversion of ER+/PR+ to ER-/PR- tumors and to study the interrelations between gene variants of ESR and IgG2-E2 in healthy women and BC patients. Polymorphic loci of ESR1 (rs2234693) and ESR2 (rs4986938) were studied by the real time PCR in 370 healthy women and 1169 BC patients. Tumor tissues ER and PR were detected by the standard immunohistochemical methods. Serum IgG2-E2 were studied using non-competitive enzyme immuno-assay. TT, TC and CC genotypes of ESR1 were revealed with the equal frequency in healthy women and BC patients I stage. Homozygotes GG of ESR2 were detected rarely, but AA frequently in BC patients with ER+/PR+ tumors at the I stage, than in healthy women женщин (44.0% and 14.2% vs 52.7 and 8.4%, respectively; p=0.005). The low levels of IgG2-ES were revealed more rarely but high levels more frequently in BC patients with ER+/PR+ tumors at the I stage, that in healthy donors (39.8% and 60.2% vs 58.0% and 42.0%, respectively; p=0.0002). Decreasing of ER+/PR+ tumors proportion and corresponding increasing of ER-/PR- tumors from I stage to II–IV stages (71.7% to 58.9% and 13.9% to 23.1%; p=0.006) were revealed in TC heterozygotes of ESR1 only. The same conversion of ER+/PR+ tumors to ER-/PR- were detected in GG homozygotes of   ESR2 (p=0.004). There have been the similar ER/PR transformation in BC patients with high IgG2-E2 levels (74.7% to 57.6% and 11.3%, to 25.0%, respectively, p<0.0001). High and low IgG2-E2 levels were detected with the same proportions at the any genotypes of ESR1 and ESR2 in healthy women or in BC patients. ESR1-2 gene polymorphisms and serum IgG2-E2 levels may be used as independent markers for prediction of ER+/PR+ and for ER+/PR+ to ER-/PR- tumors conversion during BC progression.

1. ГGlushkov A.N., Polenok E.G., Kostyanko M.V., Antonov A.V., Verzhbitskaya N.E., Vafin I.A., Ragozhina S.E. Associations of the serum antibodies to estradiol and the tumor estrogen receptors at the breast cancer patients. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2016, Vol. 10, no. 2, pp. 166-173. (In Russ.)

2. Malignant neoplasms in Russia in 2020 (morbidity and mortality). Ed. Kaprin A.D., Starinsky V.V., Shakhzadova A.O.. Moscow: P. Herzen Moscow State Medical Research Institute, Branch of the Federal State Budgetary Institution “NMIC of Radiology” of the Ministry of Health of Russia, 2021. 252 p.

3. Shashova E.E., Kondakova I.V., Slonimskaya E.M., Glushchenko S.A. Comparative study of the levels of estrogen and progesteron receptors in normal, tumor and metastatic tissues of breast cancer patients. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology, 2008, Vol. 4, no. 28, pp. 42-45. (In Russ.)

4. Borgquist S., Hjertberg M., Henningson M., Ingvar C., Rose C., Jernström H. Given breast cancer, is fat better than thin? Impact of the estrogen receptor beta gene polymorphisms. Breast Cancer Res. Treat., 2013, Vol. 137, no. 3, pp. 849-862.

5. Carrillo-Moreno D.I., Eduardo Figuera L., Zuniga González G.M., Puebla Perez A.M., Jesus Moran Mendoza A., Gallegos Arreola M.P. Association of rs2234693 and rs9340799 polymorphisms of ESR1 gene in breast cancer of Mexican population. J. BUON, 2019, Vol. 24, no. 5, pp. 1927-1933.

6. Chauhan P., Yadav R., Kaushal V., Kadian L. Evaluation of genetic polymorphism in estrogen receptor α gene as breast cancer risk. Biomed. Res., 2019, Vol. 30, no. 1, pp. 72-77.

7. Greiner M., Pfeiffer D., Smith R.D. Principles and practical application of the receiver operating characteristic analysis for diagnostic test. Prev. Vet. Med., 2000, Vol. 45, pp. 23-41.

8. Howlader N., Altekruse S.F., Li C.I., Chen V.W., Clarke C.A., Ries L.A., Cronin K.A. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl Cancer Inst., 2014, Vol. 106, no. 5, dju055. doi: 10.1093/jnci/dju055.

9. Hu X., Jiang L., Tang C., Ju Y., Jiu L., Wei Y., Guo L., Zhao Y. Association of three single nucleotide polymorphisms of ESR1 with breast cancer susceptibility: a meta-analysis. J. Biomed. Res., 2017, Vol. 31, no. 3, pp. 213-225.

10. LaCroix A.Z., Powles T., Osborne C.K., Wolter K., Thompson J.R., Thompson D.D., Allred D.C., Armstrong R., Cummings S.R., Eastell R., Ensrud K.E., Goss P., Lee A., Neven P., Reid D.M., Curto M., Vukicevic S. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J. Natl Cancer Inst., 2010, Vol. 102, no. 22, pp. 1706-1715.

11. Li Z., Yang X., Zhang R., Zhang D., Li B., Zhang D., Li Q., Xiong Y. No Association between estrogen receptor-β rs4986938 and cancer risk: a systematic review and meta-analysis. Iran. J. Public Health, 2019, Vol. 48, no. 5, pp. 784-795.

12. 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 level correlate with breast cancer cell proliferation. Oncoimmunology, 2016, Vol. 5, no. 2, e1074375-2. doi: 10.1080/2162402X.2015.1074375.

13. Sestak I. Preventative therapies for healthy women at high risk of breast cancer. Cancer Manag. Res., 2014, Vol. 6, pp. 423-430.

14. Siegel R.L., Miller K.D., Fuchs H., Jemal A. Cancer Statistics, 2022. CA Cancer J. Clin., 2022, Vol. 72, no. 1, pp. 7-33.

15. Visvanathan K., Hurley P., Bantug E., Brown P., Col N.F., Cuzick J., Davidson N.E., Decensi A., Fabian C., Ford L., Garber J., Katapodi M., Kramer B., Morrow M., Parker B., Runowicz C., Vogel V.G. III, Wade J.L., Lippman S.M. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol., 2013, Vol. 31, no. 23, pp. 2942-2962.

16. Yu K.D., Rao N.Y., Chen A.X., Fan L., Yang C., Shao Z.M. A systematic review of the relationship between polymorphic sites in the estrogen receptor-beta (ESR2) gene and breast cancer risk. Breast Cancer Res. Treat., 2011, Vol. 126, no. 1, pp. 37-45.