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Activation of Estrogen Receptor- by the Heavy Metal Cadmium

Department of Biochemistry and Molecular Biology (A.S., M.B.M.) Vincent T. Lombardi Cancer Center Georgetown University Washington, DC, 20007
Department of Molecular and Integrative Physiology (B.S.K.) University of Illinois Urbana, Illinois 61801

Previous studies from this laboratory have shown that the heavy metal cadmium (Cd) mimics the effects of estradiol in estrogen-responsive breast cancer cell lines. To understand the mechanism by which cadmium activates estrogen receptor- (ER-), the ability of cadmium to bind to and activate wild-type and various mutants of ER- was examined. When tested in transient cotransfection assays in COS-1 cells, cadmium concentrations as low as 10^-11 M activated ER-. Scatchard analysis employing either purified human recombinant ER- or extracts from ER-containing MCF-7 cells demonstrated that ¹⁰⁹Cd binds to the ER with an equilibrium dissociation constant of approximately 4 to 5 x 10^-10 M. Cadmium also blocks the binding of estradiol to ER- in a noncompetitive manner (K_i = 2.96 x 10^-10 M), suggesting that the heavy metal interacts with the hormone-binding domain of the receptor. To study the role of the hormone-binding domain in cadmium activation, COS-1 cells were transiently cotransfected with GAL-ER, a chimeric receptor containing the DNA-binding domain of the transcription factor GAL4 and the hormone-binding domain of ER-, and a GAL4-responsive reporter gene. Treatment of the transfected cells with either 10^-6 M cadmium or 10^-9 M estradiol resulted in a 4-fold increase in reporter gene activity. The effect of cadmium on the chimeric receptor was blocked by the antiestrogen, ICI-164,384, suggesting that cadmium activates ER- through an interaction with the hormone-binding domain of the receptor. Transfection and binding assays with ER- mutants identified C381, C447, E523, H524, and D538 as possible interaction sites of cadmium with the hormone-binding domain of ER-.

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