Can estrogenic radicals, generated by lactoperoxidase, be involved in the molecular mechanism of breast carcinogenesis?

Abstract

Mutations of regulatory genes, which perturb the mechanism of cell replication resulting in abnormal cell proliferation, are the main cause of cancer. Many endogenous and exogenous chemicals (including estrogenic hormones) are known to represent a major carcinogenic risk for humans. 2-OH- and 4-OH-derivatives of estrogenic molecules have been shown to form stable adducts with purine DNA bases and act as 'depurinating' agents, thus altering gene transcription (Cavalieri EL, Stack DE, Devanesan PD Proc Natl Acad Sci USA 1997; 94: 10937-10942). Lactoperoxidase (LPO), which is produced by mammary glands, is likely to be involved in breast carcinogenesis, because of its ability to interact with estrogenic hormones and oxidise them through two one-electron reaction steps. We investigated the reactivity of LPO towards five molecules: 17-β-estradiol (a natural hormone), diethylstilbestrol (a synthetic drug, supplied to pregnant women for preventing spontaneous abortion), exestrol (a synthetic antigonadotropic estrogen), 2-OH- and 4-OH-estradiol (catabolic products of estradiol). Enzymatically generated radical derivatives of such molecules were stabilized by spintrapping or by chelation of a diamagnetic metal ion and characterized with EPR spectroscopy. A kinetic study of the oxidation process was carried out using EPR and UV-visible spectroscopy.