This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martin, M. B. Articles by Stoica, A. Search for Related Content PubMed PubMed Citation Articles by Martin, M. B. Articles by Stoica, A.

Estrogen-Like Activity of Metals in Mcf-7 Breast Cancer Cells

Departments of Biochemistry and Molecular Biology (M.B.M., T.P., Y.R.A., J.C., M.L., S.D., A.S.) and Oncology, Lombardi Cancer Center (M.B.M., R.R., E.P., K.P., B.A.G., R.S.D., A.S.), Georgetown University; and Georgetown University School of Nursing and Health Studies (J.L.B., A.S.), Washington, D.C. 20007

Address all correspondence and requests for reprints to: Dr. Mary Beth Martin, Lombardi Cancer Center, Research Building E411, Georgetown University, 3970 Reservoir Rosd NW, Washington, D.C. 20007. E-mail: martinmb{at}georgetown.edu.

The ability of metals to activate estrogen receptor- (ER) was measured in the human breast cancer cell line, MCF-7. Similar to estradiol, treatment of cells with the divalent metals copper, cobalt, nickel, lead, mercury, tin, and chromium or with the metal anion vanadate stimulated cell proliferation; by d 6, there was a 2- to 5-fold increase in cell number. The metals also decreased the concentration of ER protein and mRNA by 40–60% and induced expression of the estrogen-regulated genes progesterone receptor and pS2 by1.6- to 4-fold. Furthermore, there was a 2- to 4-fold increase in chloramphenicol acetyltransferase activity after treatment with the metals in COS-1 cells transiently cotransfected with the wild-type receptor and an estrogen-responsive chloramphenicol acetyltransferase reporter gene. The ability of the metals to alter gene expression was blocked by an antiestrogen, suggesting that the activity of these compounds is mediated by ER. In binding assays the metals blocked the binding of estradiol to the receptor without altering the apparent binding affinity of the hormone (K_d = 10^-10 M). Scatchard analysis employing either recombinant ER or extracts from MCF-7 cells demonstrated that ⁵⁷Co and ⁶³Ni bind to ER with equilibrium dissociation constants of 3 and 9.5 x 10^-9 and 2 and 7 x 10^-9 M, respectively. The ability of the metals to activate a chimeric receptor containing the hormone-binding domain of ER suggests that their effects are mediated through the hormone-binding domain. Mutational analysis identified amino acids C381, C447, E523, H524, N532, and D538 as potential interaction sites, suggesting that divalent metals and metal anions activate ER through the formation of a complex within the hormone-binding domain of the receptor.

This article has been cited by other articles:

				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]

				G. Arpino, L. Wiechmann, C. K. Osborne, and R. Schiff Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance Endocr. Rev., April 1, 2008; 29(2): 217 - 233. [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]

				T Mankame, R Hokanson, R Fudge, R Chowdhary, and D Busbee Alteration of gene expression in human cells treated with the agricultural chemical diazinon: possible interaction in fetal development Human and Experimental Toxicology, May 1, 2006; 25(5): 225 - 233. [Abstract] [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]

				V. Gurel, D. A. Sens, S. Somji, S. H. Garrett, T. Weiland, and M. A. Sens Post-Transcriptional Regulation of Metallothionein Isoform 1 and 2 Expression in the Human Breast and the MCF-10A Cell Line Toxicol. Sci., June 1, 2005; 85(2): 906 - 915. [Abstract] [Full Text] [PDF]

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

				C. M Schmidt, C. N Cheng, A. Marino, R. Konsoula, and F. A Barile Hormesis effect of trace metals on cultured normal and immortal human mammary cells Toxicology and Industrial Health, February 1, 2004; 20(1-5): 57 - 68. [Abstract] [PDF]

				J. A. Fulop Integrative Tumor Board: Recurrent Breast Cancer or New Primary? Integr Cancer Ther, September 1, 2003; 2(3): 276 - 283. [PDF]