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Mary Beth Martin, Ronald Reiter, Trung Pham, Yaniris R. Avellanet, Johanna Camara, Michael Lahm, Elisabeth Pentecost, Kiran Pratap, Brent A. Gilmore, Shailaja Divekar, Ross S. Dagata, Jaime L. Bull, Adriana Stoica, Estrogen-Like Activity of Metals in Mcf-7 Breast Cancer Cells, Endocrinology, Volume 144, Issue 6, 1 June 2003, Pages 2425–2436, https://doi.org/10.1210/en.2002-221054
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Abstract
The ability of metals to activate estrogen receptor-α (ERα) 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 ERα 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 ERα. In binding assays the metals blocked the binding of estradiol to the receptor without altering the apparent binding affinity of the hormone (Kd = 10−10m). Scatchard analysis employing either recombinant ERα or extracts from MCF-7 cells demonstrated that 57Co and 63Ni bind to ERα with equilibrium dissociation constants of 3 and 9.5 × 10−9 and 2 and 7 × 10−9m, respectively. The ability of the metals to activate a chimeric receptor containing the hormone-binding domain of ERα 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 ERα through the formation of a complex within the hormone-binding domain of the receptor.
