Comprehensive immuno-hormonal assessment of the risk of breast cancer in postmenopauseal women

The study aimed to determine the personal combinations of blood serum estradiol and progesterone (E2 and Pg), classes A and G antibodies against E2, Pg and Benzo[a]pyrene (IgA₁-E2, IgA₁-Pg, IgA₁-Bp; IgG₁-E2, IgG₁-Pg, IgG₁-Bp), class G antiidiotypic antibodies to E2 and Pg (IgG₂-E2, IgG₂-Pg) levels associated with breast cancer in postmenopausal women.

Material and Methods. There were investigated 763 nonsmoking women: 206 healthy and 557 breast cancer patients (BCP) with I stage BC before treatment. The blood serum levels of hormones and antibodies were studied using competitive and non-competitive enzyme immunoassay, respectively. Statistical analysis of the results was performed using Statistica 13.0 Software, Classification and Regression Trees (CART-analysis).

Results. There were revealed 7 groups according to personal combinations of IgG₂-E2, E2, IgA₁-E2, Pg, and IgG1-Bp associated with BC risk. High E2 levels in combination with high IgG₁-Bp levels were revealed in 54.2 % of BCP vs 26.7 % of healthy women (p<0.001; OR=3.3 [2.3–4.7]). Low Pg levels in combination with low IgG1-Bp levels and average IgG2-E2 levels were more often found in BCP than in healthy women (9.9 % vs 3.9 %; p=0.01; OR=2.7 [1.3–5.8]. The various combinations of high and low levels of studied factors in others 5 groups were found in 72.4 % of healthy women and in 36.4 % of BCP. Concentrations of E2 and Pg were not correlated with studied antibodies and anti-antibodies levels. Levels of antiidiotypic antibodies were not associated with corresponding idiotypic antibodies.

Conclusion. The effect of E2 and Pg on breast cancer development was demonstrated only in combination with IgG₂-E2, IgA₁-E2, and IgG₁-Bp. Immunoassay of antibodies and antiantibodies to E2, Pg and Bp is recommended for research of chemical induced hormone-depended human carcinogenesis.

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: 10.17650/1994-4098-202319-3-16-24. EDN: BCSKSW.

2. Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer Statistics, 2022. CA Cancer J Clin. 2022; 72(1): 7–33. doi: 10.3322/caac.21708.

3. Cairns J., Ingle J.N., Dudenkov T.M., Kalari K.R., Carlson E.E., Na J., Buzdar A.U., Robson M.E., Ellis M.J., Goss P.E., Shepherd L.E., Goodnature B., Goetz M.P., Weinshilboum R.M., Li H., Bari M.G., Wang L. Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action. JCI Insight. 2020; 5(16): e137571. doi: 10.1172/jci.insight.137571.

4. Cuzick J., Sestak I., Forbes J.F., Dowsett M., Cawthorn S., Mansel R.E., Loibl S., Bonanni B., Evans D.G., Howell A.; IBIS-II investigators. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Lancet. 2020; 395(10218): 117–22. doi: 10.1016/S0140-6736(19)32955-1. Erratum in: Lancet. 2020; 395(10223): 496. doi: 10.1016/S0140-6736(20)30323-8. Erratum in: Lancet. 2021; 397(10276): 796. doi: 10.1016/S0140-6736(21)00427-X.

5. Nelson H.D., Fu R., Zakher B., Pappas M., McDonagh M. Medication use for the risk reduction of primary breast cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2019; 322(9): 868–86. doi: 10.1001/jama.2019.5780.

6. Padamsee T.J., Hils M., Muraveva A. Understanding low chemoprevention uptake by women at high risk of breast cancer: findings from a qualitative inductive study of women’s risk-reduction experiences. BMC Womens Health. 2021; 21(1): 157. doi: 10.1186/s12905-021-01279-4.

7. Archer S., Fennell N., Colvin E., Laquindanum R., Mills M., Dennis R., Stutzin Donoso F., Gold R., Fan A., Downes K., Ford J., Antoniou A.C., Kurian A.W., Evans D.G., Tischkowitz M. Personalised risk prediction in hereditary breast and ovarian cancer: a protocol for a multi-centre randomised controlled trial. Cancers (Basel). 2022; 14(11): 2716. doi: 10.3390/cancers14112716.

8. Niehoff N., White A.J., McCullough L.E., Steck S.E., Beyea J., Mordukhovich I., Shen J., Neugut A.I., Conway K., Santella R.M., Gammon M.D. Polycyclic aromatic hydrocarbons and postmenopausal breast cancer: An evaluation of effect measure modification by body mass index and weight change. Environ Res. 2017; 152: 17–25. doi: 10.1016/j.envres.2016.09.022.

9. White A.J., Chen J., McCullough L.E., Xu X., Cho Y.H., Teitelbaum S.L., Neugut A.I., Terry M.B., Hibshoosh H., Santella R.M., Gammon M.D. Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study. Cancer Causes Control. 2015; 26(12): 1791–802. doi: 10.1007/s10552015-0672-7.

10. Agudo A., Peluso M., Munnia A., Luján-Barroso L., Barricarte A., Amiano P., Navarro C., Sánchez M.J., Quirós J.R., Ardanaz E., Larrañaga N., Tormo M.J., Chirlaque M.D., Rodríguez-Barranco M., SánchezCantalejo E., Cellai F., Bonet C., Sala N., González C.A. Aromatic DNA adducts and breast cancer risk: a case-cohort study within the EPIC-Spain. Carcinogenesis. 2017; 38(7): 691–98. doi: 10.1093/carcin/bgx047.

11. Reding K.W., Han C.J., Whittington D., Zahid M., Rogan E.G., Langford D., Rohan T.E., Chlebowski R.T., Cheng T.D., Barrington W.E., Tinker L.F. Risk of breast cancer associated with estrogen DNA adduct biomarker. Cancer Epidemiol Biomarkers Prev. 2020; 29(10): 2096–99. doi: 10.1158/1055-9965.EPI-20-0133.

12. Lin C.H., Zahid M., Kuo W.H., Hu F.C., Wang M.Y., Chen I.C., Beseler C.L., Mondal B., Lu Y.S., Rogan E.G., Cheng A.L. Estrogen-DNA adducts and breast cancer risk in premenopausal Asian women. Cancer Prev Res (Phila). 2023; 16(3): 153–61. doi: 10.1158/1940-6207.CAPR-22-0415.

13. 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): 52–58. (in Russian). doi: 10.21294/1814-4861-2022-21-5-52-58. EDN: IOPEMI.

14. Hirose T., Morito K., Kizu R., Toriba A., Hayakawa K., Ogawa S., Inoue S., Hayakawa K., Muramatsu M., Hirose T., Kizu R., Masamune Y., Morito K., Inoue S., Ogawa S., Toriba A. Estrogenic/Antiestrogenic Activities of Benzo[a]pyrene Monohydroxy Derivatives. J Health Sci. 2001; 47(6): 552–58. doi: 10.1248/jhs.47.552.

15. Kang S.C., Lee B.M. Effect of estrogen receptor (ER) on benzo[a]pyrene-DNA adduct formation in human breast cancer cells. J Toxicol Environ Health A. 2005; 68(21): 1833–40. doi: 10.1080/15287390500182883.

16. Glushkov A.N., Polenok E.G., Magarill Y.A., Anosova T.P., Antonov A.V., Verzhbickaja N.E. Antibodies to benzo[a]pyrene, estradiol and progesterone in the postmenopausal breast cancer women. Siberian Journal of Oncology. 2016; 15(6): 28–34. (in Russian). doi: 10.21294/1814-4861-2016-15-6-28-34. EDN: XHJSMF.

17. 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): e1074375. doi: 10.1080/2162402X.2015.1074375.

18. Glushkov A.N., Polenok E.G., Mun S.A., Magarill Y.A., Gordeeva L.A., Lutsenko V.A., Kolpinskiy G.I., Kostyanko M.V., Vafin I.A. Effect of anti-antibodies to estradiol and progesterone on the concentration of hormones in the blood serum of healthy women and breast cancer patients. Siberian Journal of Oncology. 2020; 19(2): 62–69. (in Russian). doi: 10.21294/1814-4861-2020-19-2-62-69. EDN: DTIKEG.

19. Agaal A., Essgaer M. An Optimized Framework for Breast Cancer Prediction Using Classification and Regression Tree. MIMSE-I-C 2022, ACSR. 102: 398–412. doi: 10.2991/978-94-6463-084-8_33.

20. Glushkov A.N., Polenok E.G., Gordeeva L.A., Bayramov P.V., Verzhbitskaya N.E., Antonov A.V., Kolpinsky G.I., Kostyanko M.V. 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 Russian). doi: 10.21294/1814-4861-2024-23-3-73-85. EDN: NUDKIK.

21. De Buck S.S., Augustijns P., Muller C.P. Specific antibody modulates absorptive transport and metabolic activation of benzo[a]pyrene across Caco-2 monolayers. J. Pharmacol. Experim. Therap. 2005; 313(2): 640–46. doi: 10.1124/jpet.104.081034.

22. Grova N., Prodhomme E.J., Schellenberger M.T., Farinelle S., Muller C.P. Modulation of carcinogen bioavailability by immunisation with benzo[a]pyrene – conjugate vaccines. Vaccine. 2009; 27(31): 4142–51. doi: 10.1016/j.vaccine.2009.04.052.

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. 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 anti-estrogens and new prognostic gene signatures for breast cancer. Oncogene. 2022; 41(44): 4905–15. doi: 10.1038/s41388-022-02483-8.

25. 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.

26. Maselli A., Parlato S., Puglisi R., Raggi C., Spada M., Macchia D., Pontecorvi G., Iessi E., Pagano M.T., Cirulli F., Gabriele L., Carè A., Vici P., Pizzuti L., Barba M., Matarrese P., Pierdominici M., Ortona E. Autoantibodies specific to ERα are involved in tamoxifen resistance in hormone receptor positive breast cancer. Cells. 2019; 8(7): 750. doi: 10.3390/cells8070750.