Immuno-hormonal regulation of tumor metastasis in breast cancer patients

Aim. To determine the participation of estradiol and progesterone (E2 and Pg), hormone-specific idiotypic and antiidiotypic antibodies and antibodies against benzo[a]pyrene (Bp) in the regulation of tumor metastasis in breast cancer patients (BCP).

Materials and Methods. There were studied 475 BCP II stage (254 – without metastases and 221 – with metastases). Test-systems “ImmunoEA-Estradiol” and “ImmunoEA-Pg” (Immunotech, Moscow) were performed for blood serum E2 and Pg concentration analysis before antitumor treatment. Enzyme-linked immunosorbent assay was used for study of IgA1 and IgG1 antibodies against E2, Pg and Bp and antiidiotypic antibodies (IgG2). Associations of these serum factors with tumor metastasis were studies by CART-analysis.

Results. There were revealed the correlation of IgA1-Bp with IgA1-E2 and IgA1-Pg (rs = 0.71 and rs = 0.60; p < 0.01), IgG1-Bp with IgG1-E2 and IgG1-Pg (rs = 0.75 and r s = 0.69; p < 0.01). Concentration of E2 and Pg were no correlated with studied idiotypic and antiidiotypic antibodies levels. There was revealed 5 groups of BCP with definite personal IgG2-Pg + IgA1-Bp combinations associated with metastases significantly. Metastatic tumors were revealed in 51 BCP (group 1.1) with low levels of IgG2-Pg ≤ 2.19 cu + IgA1-Bp ≤ 2.21 cu rarely than in 137 BCP (group 2) with IgG2-Pg ≤ 2.19 cu + IgA1-Bp>2.21 cu (21.6% vs 46.0 %; p = 0,004). Metastasis were detected in 15 BCP (group 2.1) with IgG2-Pg 2.19–3.6 cu + IgA1-Bp levels ≤ 1.41cu frequently than in 199 (group 2.2) with IgG2-Pg 2.19– 3.6 cu + IgA1-Bp>1.41cu (86.7 vs 53.3; p = 0,026). Metastases were found in 73 BCP (group 3) with high IgG2-Pg>3.6 cu rarely (38.4%), vs groups 2.1 (p = 0.002) and group 2.2 (p = 0.04).

Conclusion. IgG2-Pg may inhibit whereas IgA1-Bp may stimulate the tumor metastasis in BCP II stage with definite personal combinations.

1. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. https://doi.org/10.1093/jnci/dju055

2. Strunkin DN, Kononchuk VV, Gulyaeva LF, Bogachev SS, Proskurina AS. Current aspects of systematics, diagnosis and treatment of breast cancer. Tumors of female reproductive system. 2022;18(1):25–39. (In Russ.). https://doi.org/10.17650/1994-4098-2022-18-1-25-39

3. Li Z, Wei H, Li S, Wu P, Mao X. The Role of Progesterone Receptors in Breast Cancer. Drug Des Devel Ther. 2022;16:305–314. https://doi.org/10.2147/DDDT.S336643

4. Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol. (Lausanne). 2022;13:839005. https://doi.org/10.3389/fendo.2022.839005

5. Kreipe H, Harbeck N, Christgen M. Clinical validity and clinical utility of Ki67 in early breast cancer. Ther Adv Med Oncol. 2022;14:1–10. https://doi.org/10.1177/17588359221122725

6. Zhu K, Yang X, Tai H, Zhong X, Luo T, Zheng H. HER2-targeted therapies in cancer: a systematic review. Biomark Res. 2024;12(1):16. https://doi.org/10.1186/s40364-024-00565-1

7. Autenshlyus AI, Arkhipov SA, Mikhaylova ES, Arkhipova VV, Varaksin NA. Relationship between the cytokine profle of supernatants of invasive breast carcinoma and its molecular and histopathological characteristics. Siberian Journal of Oncology. 2023;22(6):92–102. (In Russ.). https://doi.org/10.21294/1814-4861-2023-22-6-92-102

8. Studenikina AA, Mikhaylova ES, Arkhipov SA, Varaksin NA, Proskura AV, Autenshlyus AI. Blood biomarkers and Ki-67 proliferation marker in breast cancer. Medical Immunology. 2023;25(2):357–366. (In Russ.). https://doi.org/10.15789/1563-0625-BBA-2570

9. Girdhar A, Raju K, Prasad K. Association between interleukin 6 immunohistochemical and plasma levels in invasive ductal carcinoma breast: a cross-sectional study. Biomed Res Ther. 2023;10(8):5843– 5854 https://doi.org/10.15419/bmrat.v10i8.826

10. Chakraborty B, Byemerwa J, Krebs T, Lim F, Chang CY, McDonnell DP. Estrogen Receptor Signaling in the Immune System. Endocr Rev. 2023;44(1):117–141. https://doi.org/10.1210/endrev/bnac017.

11. Fedotcheva TA, Fedotcheva NI, Shimanovsky NL. Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation. Biomolecules. 2022;12(9):1299. https://doi.org/10.3390/biom12091299

12. Altwegg KA, Vadlamudi RK. Role of estrogen receptor coregulators in endocrine resistant breast cancer. Explor. Target Anti-tumor Ther. 2021;2(4):385–400. https://doi.org/10.37349/etat.2021.00052

13. 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):213–218. http://dx.doi.org/10.1530/jrf.0.0580213

14. Bochskanl R, Thie M, Kirchner CJ. Active immunization of rabbits against progesterone: increase in hormone levels, and changes in metabolic clearance rates and in genital tract tissues. Steroid Biochem. 1989;33(3):349–355. https://doi.org/10.1016/0022-4731(89)90323-3

15. 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):3464–3470. https://doi.org/10.1210/jcem.82.10.4313

16. Chaudhri RA, Schwartz N, Elbaradie K, Schwartz Z, Boyan BD. Role of ERα 36 in membrane-associated signaling by estrogen. Steroids. 2014;81:74–80. https://doi.org/10.1016/j.steroids.2013.10.020

17. Sömjen D, Kohen F, Lieberherr M. Nongenomic effects of an antiidiotypic antibody as an estrogen mimetic in female human and rat osteoblasts. J Cell Biochem. 1997;65(1):53–66. https://doi.org/10.1002/(sici)1097-4644(199704)65:1<53::aid-jcb6>3.0.co;2-y

18. Černohorská H, Klimešová S, Lepša L, Jinoch P, Milcová A, Schmuczerová J et al. Influence of immunization with non-genotoxic PAH-KLH conjugates on the resistance of organisms exposed to benzo[a]pyrene. Mut Res. 2012;742(1-2):2–10. http://dx.doi.org/10.1016/j.mrgentox.2011.10.016

19. Glushkov AN, Polenok EG, Mun SA, Gordeeva LA, Kostyanko MV, Antonov AV, et al. Personal immunological phenotype and breast cancer risk in postmenopausal women. Rus J Immunol. 2019;13(1):44– 52. (In Russ.). https://doi.org/10.31857/S102872210005019-5

20. Glushkov AN, Polenok EG, Mun SA, Gordeeva LA, Kostyanko MV, Antonov AV, et al. Tumor Ki-67, ER and PR, and antibodies against estradiol and progesterone in breast cancer patients. Fundamental and Clinical Medicine. 2023;8(3):8–17. (In Russ.). https://doi.org/10.23946/2500-0764-2023-8-3-8-17

21. Glushkov AN, Polenok EG, Gordeeva LA, Bayramov PV, Verzhbitskaya NE, Antonov AV et al. Antibodies and anti-antibodies specific to estradiol and progesterone and tumor proliferation in breast cancer patients. Siberian journal of oncology. 2024;23(3):73–85. (In Russ.). https://doi.org/10.21294/1814-4861-2024-23-3-73-85

22. Reding KW, Han CJ, Whittington D, Zahid M, Rogan EG, Langford D et al. Risk of Breast Cancer Associated with Estrogen DNA Adduct Biomarker. Cancer Epidemiol Biomarkers Prev. 2020;29(10):2096– 2099. https://doi.org/10.1158/1055-9965.EPI-20-0133

23. Sagiv SK, Gaudet MM, Eng SM, Abrahamson PE, Shantakumar S, Teitelbaum SL, et al. Polycyclic aromatic hydrocarbon-DNA adducts and survival among women with breast cancer. Environ Res. 2009;109(3):287–291. http://dx.doi.org/10.1016/j.envres.2008.11.005

24. Lin CH, Zahid M, Kuo WH, Hu FC, Wang MY, Chen IC et al. Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women. Cancer Prev Res. (Phila). 2023;16(3):153–161. https://doi.org/10.1158/1940-6207.CAPR-22-0415

25. Jerne NK. Idiotypic networks and other preconceived ideas. Immunol Rev. 1984;79:5–24. https://doi.org/10.1111/j.1600-065x.1984.tb00484.x

26. Alluri PG, Speers C, Chinnaiyan AM. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014;16(6):494–502. https://doi.org/10.1186/s13058-014-0494-7

27. Fowler AM, Salem K, DeGrave M, Ong IM, Rassman S, Powers GL et al. Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive. Breast Cancer Horm Cancer. 2020;11(2):63–75. https://doi.org/10.1007/s12672-020-00377-3

28. De Buck SS, Augustijns P, Muller CP. Specific antibody modulates absorptive transport and metabolic activation of benzo[a]pyrene across Caco-2 monolayers. J Pharmacol Experim Therap. 2005;313(2):640– 646. http://dx.doi.org/10.1124/jpet.104.081034

29. Grova N, Prodhomme EJ, Schellenberger MT, Farinelle S, Muller CP. Modulation of carcinogen bioavailability by immunization with benzo[a]pyrene – conjugate vaccines. Vaccine. 2009;27(31):4142– 4151. http://dx.doi.org/10.1016/j.vaccine.2009.04.052