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Molecular Pharmacology

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Research ArticleArticle

Estrogen Receptor α 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
Molecular Pharmacology September 2001, 60 (3) 595-602;
Marcello Maggiolini
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Daniela Bonofiglio
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Stefania Marsico
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Maria Luisa Panno
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Bruno Cenni
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Didier Picard
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Sebastiano Andò
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Abstract

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 ERα 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 ERα mRNA and protein levels. Using chimeric proteins consisting of the hormone binding domains of ERα and ERβ 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 ERα and ERβ confirm that the two phytoestrogens are ER ligands. At concentrations that are sufficient to obtain substantial transcriptional activity, they stimulate the proliferation of two ERα-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.

Footnotes

  • This work was supported by grants from Regione Calabria and U.E. (P.O.P.), MURST-CNR (Biotechnology Program L. 95/95) and from the Swiss National Science Foundation, the Krebsforschung Schweiz and the Canton de Genève.

  • Abbreviations:
    ER
    estrogen receptor
    OHT
    hydroxytamoxifen
    OHF
    hydroxyflutamide
    ZK
    ZK98299
    HBD
    hormone binding domain
    PCR
    polymerase chain reaction
    wt
    wild-type
    FCS
    fetal calf serum
    DMEM
    Dulbecco's modified Eagle's medium
    CS
    charcoal-stripped
    RT
    reverse transcription
    AF
    activation function
    • Received March 3, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Estrogen Receptor α 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
Molecular Pharmacology September 1, 2001, 60 (3) 595-602;

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Research ArticleArticle

Estrogen Receptor α 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
Molecular Pharmacology September 1, 2001, 60 (3) 595-602;
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