Anti-idiotypic antibodies specific to steroid hormones and proliferative activity of tumor in breast cancer patients

Nongenomic effects of antibodies specific to membrane steroid receptors are well known. Autoantibodies against estrogen receptor (ER) were revealed in blood serum of breast cancer patients (BCP). Their serum levels correlated with Ki-67, a protein tumor proliferation marker,. Purified antibodies stimulated in vitro proliferation of cultured MCF-7 tumor cells. Antiidiotypic antibodies against monoclonal antibodies, specific to estradiol, showed similar agonist activity. However, the function of auto-antibodies against progesterone receptor (PR) remained unknown. The purpose of this study was to search for an association between serum antiidiotypic antibodies specific to estradiol and progesterone (IgG₂-E2 and IgG₂-Pg), and expression of Ki-67 tumor protein in BCP. The IgG₂-E2 and IgG₂-Pg were studied in 204 healthy women and 663 BCP with ER⁺/PR⁺ tumors using ELISA technique with adsorbed monoclonal antibodies against E2 and Pg. Ki-67, ER and PR were detected by immunohistochemical methods. High levels of IgG₂-E2 in stage I BCP were detected more frequently than in healthy women (63.9% vs 40.2%, р < 0.001), being more common in cases with Ki-67 > 14, than with tumors with Ki-67 ≤ 14 (63.9% vs 56.9%, р = 0.03). Similar association of IgG₂- Pg with Ki-67 was not revealed. The individually low levels of both IgG₂-E2 and IgG₂-Pg in stage I BCP with Ki-67 ≤ 14 tumors were found in 55.2%, compared to 22.4% in cases with Ki-67 > 30. The cooperatively high IgG₂-E2 and IgG₂-Pg levels were detected in 35.7% of stage I BCP with Ki-67 ≤ 14 tumors and in 28.6% with Ki-67 > 30 cases (p = 0.03). On the contrary, high IgG₂-E2 levels in BCP II-IV stages with tumor Ki-67 > 30 were less comon, than with Ki-67 ≤ 14 (49.1% vs 64.2%, р = 0.03). Similar association was found with IgG₂-Pg (47.2% vs 62.2%, р = 0.03). The cooperatively high individual IgG₂- E2 and IgG₂-Pg levels were detected in BCP at II-IV stages with Ki-67 ≤ 14 and Ki-67 > 30 (respectively, 38.0% and 37.0). These indices comprised 21.5% and 53.9% when the levels of studied antibodies were low (p = 0.003). In conclusion, high individual levels of both IgG₂-E2 and IgG₂-Pg were associated with high proliferative activity of ER⁺/PR⁺ breast cancer at initial tumor growth (stage I), and with low proliferation rates at subsequent tumor growth (stages II-IV).

1. 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. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2023, Vol. 25, no. 1, pp. 35-48. (In Russ.) doi: 10.46235/1028-7221-1177-CO.

2. Brown J., Scardo S., Method M., Schlauch D., Misch A., Picard S., Hamilton E., Jones S., Burris H., Spigel D. A real-world retrospective study of the use of Ki-67 testing and treatment patterns in patients with HR+, HER2-early breast cancer in the United States. BMC Cancer, 2022, Vol. 22, no. 1, 502. doi: 10.1186/s12885-022-09557-6.

3. Dressing G.E., Goldberg J.E., Charles N.J., Schwertfeger K.L., Lange C.A. Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications. Steroids, 2011, Vol. 76, no. 1-2, pp. 11-17.

4. 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.

5. Hacking S.M., Wang Y. Practical issues of Ki-67 evaluation in breast cancer clinical practice. J. Clin.Transl. Pathol., 2022, Vol. 2, no. 2, pp. 53-56.

6. Kampa M., Notas G., Pelekanou V., Troullinaki M., Andrianaki M., Azariadis K., Kampouri E., Lavrentaki K., Castanas E. Early membrane initiated transcriptional effects of estrogens in breast cancer cells: First pharmacological evidence for a novel membrane estrogen receptor element (ERx). Steroids, 2012, Vol. 77, no. 10, pp. 959-967.

7. Kim J.Y., Han W., Moon H.G., Ahn S.K., Kim J., Lee J.W., Kim M.K., Kim T., Noh D.Y. Prognostic effect of preoperative serum estradiol level in postmenopausal breast cancer. BMC Cancer, 2013, Vol. 13, 503. doi: 10.1186/1471-2407-13-503.

8. Li Q., Gao H., Yang H., Wei W., Jiang Y. Estradiol promotes the progression of ER+ breast cancer through methylation-mediated RSK4 inactivation. Onco Targets Ther., 2019, Vol. 12, pp. 5907-5916.

9. 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, Vol. 69, no. 8-9, pp. 553-559.

10. 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, pp. e1074375. doi: 10.1080/2162402X.2015.1074375.

11. Mohammed H., Russell I.A., Stark R., Rueda O.M., Hickey T.E., Tarulli G.A., Serandour A.A., Birrell S.N., Bruna A., Saadi A., Menon S., Hadfield J., Pugh M., Raj G.V., Brown G.D., D’Santos C., Robinson J.L., Silva G., Launchbury R., Perou C.M., Stingl J., Caldas C., Tilley W.D., Carroll J.S. Progesterone receptor modulates ERα action in breast cancer. Nature, 2015, Vol. 523, no. 7560, pp. 313-317.

12. 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, Vol. 14, no. 1, pp. 157-165.

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.E., Jemal A. Cancer statistics, 2022. CA Cancer J. Clin., 2022, Vol. 72, no. 1, pp. 7-33.

15. 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, Vol. 65, no. 1, pp. 53-66.