4-hydroxyestradiol and Endometrial-Neoplasms

Increased levels of endogenous estrogens and their metabolites are well-known risk factors of endometrial cancer. The aim of this study was to quantitatively assess the potential for estrogen metabolites to serve as biomarkers of endometrial carcinogenesis. The following estrogen metabolites were evaluated: 2-hydroxyestradiol (2-OHE2), 2-hydroxyestrone (2-OHE1), 4-hydroxyestradiol (4-OHE2), 4-hydroxyestrone (4-OHE1), 16α-hydroxyestrone (16α-OHE1), 2-methoxyestradiol (2-MeOE2), and 2-methoxyestrone (2-MeOE1). The low content of estrogen metabolites in urine makes their measurement difficult. To address this issue, we developed a rapid, sensitive, specific, and accurate liquid chromatography-mass spectrometry (LC-MS) method, with hollow fiber liquid-phase micro-extraction (HF-LPME) for an enriched pretreatment of the sample and for the simultaneous quantification of estrogens and their metabolites in the urine samples of 23 post-menopausal female endometrial cancer patients and 23 post-menopausal healthy female controls. The levels of estrogens were found to differ between the endometrial cancer patients and the controls. The level of 4-OHE2 was elevated in patients compared with the controls, while the levels of 2-MeOE1 and 2-MeOE2 were reduced in the endometrial cancer group. The results of this study indicate an imbalance of estrogen metabolites in endometrial carcinogenesis, and that the elevation of 4-OHE2 may be used as a potential biomarker for the risk assessment of estrogen-induced endometrial cancer.

Topics: Biomarkers, Tumor; Chromatography, Liquid; Endometrial Neoplasms; Estrogens; Estrogens, Catechol; Female; Humans; Mass Spectrometry; Middle Aged

The development of hormone-dependent cancers, including endometrial carcinomas, in great part may be mediated by the genotoxic effects of estrogen metabolites, among which 4-hydroxyestradiol (4OHE2) is characterized by the most prominent DNA-damaging properties. It is assumed that the individual sensitivity to the 4OHE2 may determine the predisposition to endometrial cancer (EС).. To analyze the sensitivity of peripheral blood lymphocytes (PBLs) of EC patients to the 4OHE2 and to evaluate the repair efficiency of 4OHE2-induced DNA damage.. The study was performed on the PBLs of 53 EC patients and 20 healthy women. The level of DNA damage was measured using the comet assay and was expressed as % tail DNA. The DNA repair efficiency (%) was evaluated by determining the ratio between the amount of repaired DNA damage and the level of 4OHE2-induced damage that appeared after incubation of PBLs with 4OHE2.. In PBLs of EC patients, a higher level of 4OHE2-induced DNA damage (32.0 ± 2.2% tail DNA) and lower DNA repair efficiency (34.0 ± 4.5%) was observed compared to PBLs of healthy women (22.3 ± 2.3% tail DNA and 48.8 ± 4.5%, respectively). PBLs of EC patients with deep tumor invasion of myometrium were characterized by more prominent decrease of DNA repair than those with less invasive tumor (< ½ of myometrium) (20.9 ± 7.8 and 43.7 ± 6.7%, respectively). Furthermore, lower DNA repair efficiency was detected in the PBLs of EC patients with a family history of cancer compared to this parameter in patients with sporadic tumors (20.9±7.8 and 47.1 ± 5.5%, respectively).. The PBLs of EC patients are characterized by increased sensitivity to the genotoxic effect of 4OHE2 and reduced repair efficiency regarding 4OHE2-induced DNA damage. A lower level of DNA repair is observed in EC patients with deep tumor myometrial invasion and a family history of cancer.

Topics: Adult; Aged; Carcinoma, Endometrioid; DNA Damage; DNA Repair; Endometrial Neoplasms; Estrogens, Catechol; Female; Humans; Lymphocytes; Middle Aged; Mutagens

UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E(2)) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E(2) and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)(7)TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses' Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)(6)TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56-1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21-0.75) for the homozygous UGT1A1*28 genotype (P(trend) = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18-0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55-1.13) for postmenopausal women who carry the UGT1A1*28 allele (P(interaction) = 0.05)]. These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E(2), in the endometrium.

Topics: Adult; Alleles; Endometrial Neoplasms; Endometrium; Estradiol; Estrogens, Catechol; Female; Glucuronides; Glucuronosyltransferase; Humans; Middle Aged; Polymorphism, Genetic; Promoter Regions, Genetic; Substrate Specificity