Induction and repair of 4-OHEN-DNA adducts in human breast cancer cells by the metabolites of equine estrogens

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Hormone replacement therapy (HRT) is widely used to decrease menopausal symptoms in post-menopausal women. However, long-term HRT increases the incidence of breast, ovarian and endometrial cancers. 4-Hydroxyequilenin (4-OHEN), a metabolite of equine estrogens present in common HRT formulations (Premarin), is capable of producing bulky 4-OHEN-DNA adducts. An immunological assay using our adduct-specific antibodies revealed that 4-OHEN-DNA adducts are repaired inefficiently in human breast cancer cells. MTS assay revealed that similar 4-OHEN sensitivities are observed between human normal and repair-deficient cells. Moreover, histones including human H1 competitively inhibited the binding of the antibodies to 4-OHEN-DNA adducts in a concentration-dependent manner, which are considered as a model of damage-recognising repair protein. Thus, the formation of DNA adducts with inefficient repair character might be involved in carcinogenesis process of Premarin-induced cancers.