Immunological imbalance, gene polymorphism of biotransformation enzymes, and steroid hormone receptors in tumors in breast cancer patients

Abstract

It is well known that results of breast cancer (BC) hormonal therapy depend on expression of tumor estradiol and progesterone receptors (ER and PR) in tumor tissue. Mechanisms of ER+/PR+ tumors conversion to ER+/PR- and ER-/PR- tumors remain scarcely studied. The decrease of steroid receptors expression seems to depend on action of genotoxic metabolites of environmental carcinogens (particularly, benzo[a]pyrene, BP) and endogenous steroids (in particular, estradiol, E2). The formation of these metabolites is regulated by the biotransformation enzymes. On the other hand, the formation of DNA-adducts with genotoxic metabolites may induce the synthesis of specific antibodies. Previously, it was shown that increase of the serum IgA-antibodies levels against Bp and E2 over the levels of IgA-antibodies against progesterone (IgA-Bp/IgA-Pg > 1 and IgA-E2/IgA-Pg), could be interpreted as immunological imbalance associated with high BC risk in healthy women. The purpose of this study was to detect the suggested associations between ER+/PR+ tumors conversion to ER+/PR+ and ER-/PR- tumors and immunological imbalance in the BC patients with distinct gene variants of biotransformation enzymes: CYP1A1*2A (rs 4646903), CYP1B1 (rs1056836), CYP19A1 (rs2470152), GSTT1 (del), GSTP1 (rs1695). The IgA-Bp, IgA-E2 and IgA-Pg were studied in 1321 non-smoking BC patients by non-competitive solid phase immunoassay. The conjugates of Bp, E2 and Pg with bovine serum albumin were adsorbed as target antibodies. The goat antibodies against human IgA conjugated with horseradish peroxidase were used for detection of the studied specific antibodies. Gene polymorphisms of biotransformation enzymes were analyzed by the real-time PCR. Tumor ER and PR were detected by the standard immunohistochemical methods.ER+/PR+ tumors in BC patients at the stage I (N = 534) were found in 68.7%, ER+/PR- in 15.6%, ER-/ PR- in 15.7%. In BC patients at the II-IV stage (N = 787), frequency of ER+/PR+ tumors decreased to 60.2%, ER+/PR- was similar (15.8%), and ER-/PR- increased to 24.0% (p < 0.0001). These alterations were revealed in BC patients at the IgA-Bp/IgA-Pg ratios > 1, and IgA-E2/IgA-Pg > 1 only. There were no differences found between BC patients at stage I and II-IV at the ER+/PR+, ER+/PR-, ER-/PR- frequencies when these ratios were low.The frequency of ER+/PR+ tumors in homozygotes TT of CYP19A1 was 77.1% at the I stage and 60.1% at the II-IV stages. Respectively the frequencies of ER-/PR- tumors were 11.8% and 26.1% (p < 0.001). ER+/ PR+ tumors were revealed in GSTT1 “+” BC patients at the I stage in 68.7% and at the II-IV stages in 58.0%. Respectively ER-/PR- tumors were found in 16.6% and 24.5% (p < 0.0004). The frequency of ER+/PR+ tumors was 57.1% in homozygotes GG of GSTP1 at the I stage and 60.7% at the II-IV stages. Respectively the frequencies of ER+/PR- were 14.3% and 22.2% and ER-/PR- were 28.6% and 19.0% (p < 0.001). Proportions of low and high IgA-Bp/IgA-Pg and IgA-E2/IgA-Pg ratios were the same at the any enzyme genotype of studied CYP or GST variants. In conclusion, we have revealed a sufficient contribution of immunological imbalance to the conversion of steroid receptors in breast cancer growth, being independent of several CYP and GST gene polymorphisms.