Antibodies and anti-antibodies specific to estradiol and progesterone and tumor proliferation in breast cancer patients

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.

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. Modi D.N., Shah C., Puri C.P. Non-genomic membrane progesterone receptors on human spermatozoa. Soc Reprod Fertil Suppl. 2007; 63: 515–29.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. Jerne N.K. Idiotypic networks and other preconceived ideas. Immunol Rev. 1984; 79: 5–24. doi: 10.1111/j.1600-065x.1984.tb00484.x.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.