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Eur J Cancer Prev. 1997 Feb;6(1):3-10.

Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens.

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1
Department of Pharmacology, University of Texas Medical Branch, Galveston 77555-1031, USA.

Abstract

Epidemiological evidence increasingly points to exogenous or endogenous oestrogens as a risk factor for breast cancer. However, it is unlikely that induction of oestrogen-dependent tumour growth is the sole contribution of oestrogens to tumour development in the mammary gland, because oestrogen receptors are barely detectable in normal mammary epithelial cells. In this review, I examine a mechanism for mammary carcinogenesis, which emphasizes tumour initiation by metabolic activation of oestrogens in combination with cell transformation and growth stimulation by oestrogen receptor-mediated processes. Catecholestrogen metabolites are capable of metabolic redox cycling between quinone and hydroquinone forms, a mechanism of free radical generation. Several types of direct and indirect free radical-mediated DNA damage are induced by oestrogens in vitro and in vivo, such as DNA single strand breaks, 8-hydroxylation of guanine bases, and DNA adduct formation by malondialdehyde, a decomposition product of free radical-induced lipid peroxides. The substrate for redox cycling and free radical generation may be 4-hydroxoestradiol, because this metabolite is formed from oestradiol by a specific oestrogen 4-hydroxylase detected in several human organs including mammary tissue. It has also been formed in organs of rodents where oestrogens induce tumours, with the exception of the liver. 4-Hydroxyoestradiol is a potent, long-acting oestrogen and may complete the carcinogenic process by stimulating receptor-mediated proliferation. An understanding of a possible mechanism of mammary carcinogenesis as a result of oestrogen-mediated initiation means that several prevention strategies, based on inhibiting metabolic activation of oestrogens or free radical action, can be developed.

[Indexed for MEDLINE]

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