Association of estrogen metabolism and risk of breast or prostate cancer or non-Hodgkin lymphoma: Detection of novel biomarkers from case-control studies.

摘要

The precise molecular mechanism by which estrogens play a role in the initiation of breast cancer (BC), prostate cancer (PC) and non-Hodgkin lymphoma (NHL) has been in question. We hypothesize that specific estrogen metabolites, catechol estrogen-3,4-quinones [E1(E2)-3,4-Q], can bind with DNA to form 4-OHE1(E2)-N7Gua and 4-OHE 1(E2)-N3Ade adducts; apurinic sites that are formed by depurination of these adducts can induce mutations by error-prone repair. When homeostasis of estrogen metabolism is disrupted and oxidative estrogen metabolism prevails in the body, then the risk of the above diseases will be increased. To test this hypothesis, I have conducted BC, PC and NHL case-control studies to investigate how imbalance of estrogen metabolism affects the etiology of the above diseases and try to find potential early biomarkers in biological samples (serum and urine). This was accomplished by partial purification of biological samples with a solid phase extraction method and analysis by ultra-performance liquid chromatography/tandem mass spectrometry to assay 40 estrogen related compounds. The results show that there are significantly higher levels of depurinating estrogen-DNA adducts in the BC, PC and NHL cases than in the controls. In addition, the ratios of the sum of depurinating estrogen-DNA adducts to the sum of their corresponding estrogen metabolites and conjugates, which reflects the extent of imbalance of estrogen metabolism in the body, were significantly higher in the cases than in the controls. We conclude that formation of E 1(E2)-3,4-Q, which arise from an imbalance in estrogen metabolism, plays a very important role in the etiology of the above diseases. The ratios can be utilized as novel biomarkers to predict the risk and provide targeted strategies of BC, PC and NHL prevention in clinic settings.