Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E2) is thought to be oxidized to 4-hydroxyestradiol and then to E2-3,4- quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E2-3,4-quinone can undergo redox cycling with E2-3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E 2-3,4-quinone are carcinogenic or mutugenic in several systems, 4-hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-hydroxyestradiol is mutagenic in the cll assay in BB rat2 cells. Under similar conditions, 2-hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E2-3,4- quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.
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