Mechanisms underlying endocrine disruption and breast cancer

This article reviews the effects of Endocrine Disrupters (EDs) on cancer incidence in humans, the analysis being practically restricted to the influence of xenoestrogens on the occurrence of breast cancer. Although receptor-mediated mechanisms play an important role in eliciting the effects of (xeno)oestrogens (XEs), it should not be overlooked that other pathways exist, and that any evaluation must therefore consist of the net result of all influences. It is not acceptable to base the evaluation of the effects of xenoestrogens, or their inclusion in the category of EDs, solely on their property to bind the oestrogen receptor (ER). Other mechanisms contribute in eliciting the oestrogenic response and are briefly reviewed. They include serum factors; the binding to carrier proteins; alterations in metabolic pathways; interactions between oestrogens; growth factors and their receptors and oncogenes; disturbances in signal transduction pathways and interference with several accessory mechanisms of carcinogenesis. The particular carcinogenesis mechanisms underlying the action of (xeno)oestrogens are discussed. This mechanism implicates the absence of any threshold and-consequently-inducing effects at the lowest possible concentrations: one molecule. Other factors influencing the effects of XEs are represented by the occurrence of a membrane oestrogen receptor, different from the traditional nuclear ER, participating in the regulation of Prolactin production by the hypophysis after stimulation of the hypothalamic-hypophyseal pathways. Strong co-operation also exists with thyroid hormones. Many epidemiological studies, of which some are critically reviewed, support the basic role of XEs as one of the causative factors of breast cancer. This only serves to underscore the compulsory application of the precautionary principle, once a compound has been proven to exert endocrine disrupting properties, and the necessity to evaluate all modes of action of EDs.