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Vol. 60, Issue 3, 595-602, September 2001

Estrogen Receptor alpha  Mediates the Proliferative but Not the Cytotoxic Dose-Dependent Effects of Two Major Phytoestrogens on Human Breast Cancer Cells

Marcello Maggiolini, Daniela Bonofiglio, Stefania Marsico, Maria Luisa Panno, Bruno Cenni, Didier Picard, and Sebastiano Andò

Departments of Pharmaco-Biology (M.M., D.B.) and Cellular Biology (S.M., M.L.P., S.A.), University of Calabria, Rende-Cosenza, Italy; and Département de Biologie Cellulaire, Université de Genève, Sciences III, Genève, Switzerland (B.C., D.P.)

Phytoestrogens are a chemically diverse group of compounds made by plants that can have estrogenic effects in animals. Both tumorigenic and antitumorigenic effects have been reported. Although estrogens stimulate the growth of many breast tumors, there is a negative correlation between the incidence of breast cancer and the phytoestrogen-rich diet of certain Asian populations. To begin to resolve this paradox, we have analyzed the estrogenic properties of genistein and quercetin, two flavonoid phytoestrogens particularly abundant in soybeans. Trans-activation experiments with a transfected reporter gene for nuclear estrogen receptors (ER) show strong activation of the endogenous ERalpha by both phytoestrogens in two MCF7 human breast cancer cell lines. This is supported by the observation that the two phytoestrogens induce the down-regulation of ERalpha mRNA and protein levels. Using chimeric proteins consisting of the hormone binding domains of ERalpha and ERbeta fused to the Gal4 DNA binding domain, we have established that genistein and quercetin are full estrogenic agonists of both ER isoforms. Ligand binding experiments with purified ERalpha and ERbeta confirm that the two phytoestrogens are ER ligands. At concentrations that are sufficient to obtain substantial transcriptional activity, they stimulate the proliferation of two ERalpha -dependent breast cancer cell lines. At high concentrations, such as those reached with a soy-rich diet, genistein and quercetin are strong cytotoxic agents that even kill ER-independent HeLa cells. Thus, the mode of action of phytoestrogens and the balance between being risk or chemopreventive factors for breast cancer may depend on the dietary load.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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