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Laboratory evaluation of estrogen metabolism - Estrogen Metabolism
28/11/2011 06:53:08

Higher levels of estradiol (E2), and especially estrone (E1), in serum and urine have been consisten...

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Estrogen-Like Activity of Metals in Mcf-7 Breast Cancer Cells
11/05/2011 09:42:23

The ability of metals to activate estrogen receptor- (ER ) ...

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PREVENÇÃO & SAUDE - Antonio Pacileo Cruz, Solange Frazão, Tatiana Cunha



Nutrição Cerebral - Dr. Juarez Callegaro no Programa Abraão Winogrom

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Estrogen-Like Activity of Metals in Mcf-7 Breast Cancer Cells 11/05/2011 09:42:23

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 (Kd  1010 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  109 and 2 and 7  109 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 hormonebinding
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. (Endocrinology 144: 2425–2436, 2003)

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