Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development

Oestrogens, including the natural hormones oestrone and oestradiol, induce various tumours in laboratory animals and have been recognized to be carcinogens in humans, raising the risk for breast and uterine cancer. As part of the search for the mechanism of hormone-induced carcinogenesis, various types of DNA damage have been detected which have been induced by oestrogens in cell-free systems, in cells in culture, or in vivo. Nevertheless, oestrogens have been postulated to act only as promoters of mammary carcinogenesis by receptor-mediated growth stimulation without consideration of their genotoxicity because these hormones failed to induce mutations in commonly used assays. More recently, oestradiol-induced numerical chromosomal changes (aneuploidy) and structural chromosomal aberrations have been detected in cells in culture and in hamster kidney, a target of oestrogen-induced cancer. In this animal model, oestradiol generates c-myc gene amplification and microsatellite instability. Mutations of the hprt gene have been induced by oestradiol in V79 cells and by catecholoestrogen metabolites in Syrian hamster embryo cells. Sequencing of this gene isolated from V79 mutant clones revealed point mutations and deletions. It is concluded that oestradiol plays a dual role as mutagen/carcinogen and as growth-stimulating hormone in the induction of tumours.