Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells.
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Maggiolini M, Bonofiglio D, Marsico S, Panno ML, Cenni B, Picard D, Ando S
Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells.
Mol Pharmacol. 2001 Sep;60(3):595-602.
- PubMed ID
- 11502892 [ View in PubMed]
- 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 ER alpha 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 ER alpha mRNA and protein levels. Using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta 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 ER alpha and ER beta confirm that the two phytoestrogens are ER ligands. At concentrations that are sufficient to obtain substantial transcriptional activity, they stimulate the proliferation of two ER alpha-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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Quercetin Estrogen receptor alpha Protein Humans UnknownNot Available Details Quercetin Estrogen receptor beta Protein Humans UnknownNot Available Details - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Genistein Investigational ESR1 2099 downregulated Genistein results in decreased expression of ESR1 mRNA 6q25.1-q25.2 Quercetin Experimental Investigational ESR1 2099 downregulated Quercetin results in decreased expression of ESR1 mRNA 6q25.1-q25.2