Estrogen-induced genetic alterations and their role in carcinogenicity

The oxidation of catechol metabolites (2-OH-E1/2/3 and 4-OH-E1/2/3) of the endogenous estrogen, i.e. estrone (E1), 17 beta-estradiol (E2), estriol (E3), gives rise to corresponding estrogen-2.3-quinone (E-2,3-Q) and estrogen-3,4-quinone (E-3,4-Q). These reactive estrogen metabolites form covalent adducts with DNA and quinone, and semi-quinone forms of catechol estrogens-induced DNA adducts are found in various target tissues of cancer. Catecholestrogen through redox cycling produce free radicals that also generate various forms of free radical-induced DNA damage. Interaction of estrogen-induced oxidants and estrogen metabolites with DNA has been shown to generate mutations in genes. Hypermethylation at CpG sites in specific regions of the genome coupled with estrogen-induced oxidative damage at CpG sites, predominantly in the hypermethylated regions, could also cause alterations in the genome of cells of estrogen target organs that lead to mutation of genes. Increasing evidence shows that estrogen through oxidative stress and/or its metabolic products induce genetic alteration affecting both the structural as well as function of the genes. Presence of multiple forms of genetic alterations such as chromosomal aberrations, gene amplifications, DNA sequence variations, and DNA microsatellite instability in estrogen-related cancers and induction of similar genetic events by estrogen both in vivo and in vitro indicate that genetic alterations play an important role in estrogen-related carcinogenesis. This review highlights the current understanding of the estrogen-induced genetic alterations and their significance in estrogen-related carcinogenesis.