Interactions of isoflavones and other plant derived estrogens with estrogen receptors for prevention and treatment of breast cancer-considerations concerning related efficacy and safety.

Phytoestrogens are natural endocrine disruptors that interfere with estrogenic pathways. They insert directly within the hormone-binding domain of ERα and β, with a preference for the β isoform of which the concentration predominates in the normal mammary epithelium. Since ERβ antagonizes the growth promoting effect of ERα, which is mainly expressed in estrogen-sensitive tumor cells, a potential protective action against breast cancer incidence has been ascribed to phytoestrogens. The fact that Asian women living in far-east countries who consume isoflavone-rich food are less subjected to breast cancer emergence than their congeners in the USA as well as Caucasian women has been advocated to justify such a concept. Overview of data concerning the mechanism of action phytoestrogens reveals that such a view is an oversimplification: Such compounds interfere with a huge panel of regulatory proteins, giving rise to both promoting and antagonizing carcinogenic effects. Moreover, various physiological and pathological factors able to amplify these effects are not often sufficiently taken into account, which increases the difficulty to interpret data. Nevertheless, this overview of data established that chemical structures and concentrations modulate such effects: at the micromolar level, isoflavones activate ERα-mediated transcription and breast cancer cell proliferation while flavones fail to induce any significant promoting effects. At higher doses, both classes of compounds may display an antitumor activity. Reasons for such distinct behaviors as well as their potential impact in therapeutic applications are analyzed here. Ability of isoflavones and flavones to antagonize the association of calmodulin to ERα, which is required for its enhanced transcriptional activity is evoked to justify the antitumor activity ascribed to some flavones. Finally, a suspicion that peculiar classes of phytoestrogens may adopt a SERM-like conformation is addressed in a context of selection and synthesis of compounds with non-equivocal therapeutic value. This article is part of a Special Issue entitled "Phytoestrogens".