This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stoica, A. Articles by Martin, M. B. Search for Related Content PubMed PubMed Citation Articles by Stoica, A. Articles by Martin, M. B.

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-.

This article has been cited by other articles:

				A. Akesson, B. Julin, and A. Wolk Long-term Dietary Cadmium Intake and Postmenopausal Endometrial Cancer Incidence: A Population-Based Prospective Cohort Study Cancer Res., August 1, 2008; 68(15): 6435 - 6441. [Abstract] [Full Text] [PDF]

				D. J. Veselik, S. Divekar, S. Dakshanamurthy, G. B. Storchan, J. M.A. Turner, K. L. Graham, L. Huang, A. Stoica, and M. B. Martin Activation of Estrogen Receptor-{alpha} by the Anion Nitrite Cancer Res., May 15, 2008; 68(10): 3950 - 3958. [Abstract] [Full Text] [PDF]

				L.W. Jackson, M.D. Zullo, and J.M. Goldberg The association between heavy metals, endometriosis and uterine myomas among premenopausal women: National Health and Nutrition Examination Survey 1999-2002 Hum. Reprod., March 1, 2008; 23(3): 679 - 687. [Abstract] [Full Text] [PDF]

				M. B. Martin, R. Reiter, M. Johnson, M. S. Shah, M. C. Iann, B. Singh, J. K. Richards, A. Wang, and A. Stoica Effects of Tobacco Smoke Condensate on Estrogen Receptor-{alpha} Gene Expression and Activity Endocrinology, October 1, 2007; 148(10): 4676 - 4686. [Abstract] [Full Text] [PDF]

				K. Lehnes, A. D. Winder, C. Alfonso, N. Kasid, M. Simoneaux, H. Summe, E. Morgan, M. C. Iann, J. Duncan, M. Eagan, et al. The Effect of Estradiol on in Vivo Tumorigenesis Is Modulated by the Human Epidermal Growth Factor Receptor 2/Phosphatidylinositol 3-Kinase/Akt1 Pathway Endocrinology, March 1, 2007; 148(3): 1171 - 1180. [Abstract] [Full Text] [PDF]

				N. Kitana, S. J. Won, and I. P. Callard Reproductive Deficits in Male Freshwater Turtle Chrysemys picta from Cape Cod, Massachusetts Biol Reprod, March 1, 2007; 76(3): 346 - 352. [Abstract] [Full Text] [PDF]

				D. J. Adle, D. Sinani, H. Kim, and J. Lee A Cadmium-transporting P1B-type ATPase in Yeast Saccharomyces cerevisiae J. Biol. Chem., January 12, 2007; 282(2): 947 - 955. [Abstract] [Full Text] [PDF]

				S. Pillet, M. D'Elia, J. Bernier, J.-M. Bouquegneau, M. Fournier, and D. G. Cyr Immunomodulatory Effects of Estradiol and Cadmium in Adult Female Rats Toxicol. Sci., August 1, 2006; 92(2): 423 - 432. [Abstract] [Full Text] [PDF]

				J. A. McElroy, M. M. Shafer, A. Trentham-Dietz, J. M. Hampton, and P. A. Newcomb Cadmium exposure and breast cancer risk. J Natl Cancer Inst, June 21, 2006; 98(12): 869 - 873. [Abstract] [Full Text] [PDF]

				K. Yang, L. Julan, F. Rubio, A. Sharma, and H. Guan Cadmium reduces 11{beta}-hydroxysteroid dehydrogenase type 2 activity and expression in human placental trophoblast cells Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E135 - E142. [Abstract] [Full Text] [PDF]

				M Nasiadek, T Krawczyk, and A Sapota Tissue levels of cadmium and trace elements in patients with myoma and uterine cancer Human and Experimental Toxicology, December 1, 2005; 24(12): 623 - 630. [Abstract] [PDF]

				C. Nagata, Y. Nagao, C. Shibuya, Y. Kashiki, and H. Shimizu Urinary Cadmium and Serum Levels of Estrogens and Androgens in Postmenopausal Japanese Women Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 705 - 708. [Abstract] [Full Text] [PDF]

				A. Novillo, S.-J. Won, C. Li, and I. P. Callard Changes in Nuclear Receptor and Vitellogenin Gene Expression in Response to Steroids and Heavy Metal in Caenorhabditis elegans Integr. Comp. Biol., January 1, 2005; 45(1): 61 - 71. [Abstract] [Full Text] [PDF]

				A. Vetillard and T. Bailhache Cadmium: An Endocrine Disrupter That Affects Gene Expression in the Liver and Brain of Juvenile Rainbow Trout Biol Reprod, January 1, 2005; 72(1): 119 - 126. [Abstract] [Full Text] [PDF]

				M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]

				V. S. Wilson, K. Bobseine, and L. E. Gray Jr. Development and Characterization of a Cell Line That Stably Expresses an Estrogen-Responsive Luciferase Reporter for the Detection of Estrogen Receptor Agonist and Antagonists Toxicol. Sci., September 1, 2004; 81(1): 69 - 77. [Abstract] [Full Text] [PDF]

				M. C. Henson and P. J. Chedrese Endocrine Disruption by Cadmium, a Common Environmental Toxicant with Paradoxical Effects on Reproduction Exp Biol Med, May 1, 2004; 229(5): 383 - 392. [Abstract] [Full Text] [PDF]

				M. B. Martin, R. Reiter, T. Pham, Y. R. Avellanet, J. Camara, M. Lahm, E. Pentecost, K. Pratap, B. A. Gilmore, S. Divekar, et al. Estrogen-Like Activity of Metals in Mcf-7 Breast Cancer Cells Endocrinology, June 1, 2003; 144(6): 2425 - 2436. [Abstract] [Full Text] [PDF]

				G. E. Stoica, T. F. Franke, A. Wellstein, F. Czubayko, H.-J. List, R. Reiter, E. Morgan, M. B. Martin, and A. Stoica Estradiol Rapidly Activates Akt via the ErbB2 Signaling Pathway Mol. Endocrinol., May 1, 2003; 17(5): 818 - 830. [Abstract] [Full Text] [PDF]

				M. B. Martin, H. J. Voeller, E. P. Gelmann, J. Lu, E.-G. Stoica, E. J. Hebert, R. Reiter, B. Singh, M. Danielsen, E. Pentecost, et al. Role of Cadmium in the Regulation of AR Gene Expression and Activity Endocrinology, January 1, 2002; 143(1): 263 - 275. [Abstract] [Full Text] [PDF]

				J. A. McLachlan Environmental Signaling: What Embryos and Evolution Teach Us About Endocrine Disrupting Chemicals Endocr. Rev., June 1, 2001; 22(3): 319 - 341. [Abstract] [Full Text] [PDF]