Effects of selenite on estrogen receptor-? expression and activity in MCF-7 breast cancer cells

Abstract

To determine whether selenite has estrogen-like activities, the effects of this compound on estrogen receptor-alpha (ER-alpha) and other estrogen-regulated genes were measured in the human breast cancer cell line MCF-7. Treatment of cells with 1 uM of sodium selenite resulted in a 40% decrease in the amount of estrogen receptor-alpha and in a parallel decrease of 40% in ER-alpha mRNA. Progesterone receptor concentration increased 2.6-fold and pS2 mRNA increased 2.4-fold after selenite treatment. The induction of progesterone receptor and pS2 was blocked by the anti-estrogen ICI-182,780. In transient co-transfection experiments of Wild-type ER-alpha and an estrogen response element-reporter construct, selenite stimulated CAT activity. In binding assays, selenite blocked the binding of estradiol to ER-alpha (K(i) = 23 +/- 17 nM, n = 3) suggesting that this compound interacts with the hormone binding domain of the receptor. To determine whether interaction of selenite with the hormone binding domain results in receptor activation, COS-1 cells were transiently co-transfected with the chimeric receptors GAL-ER, which contains the hormone binding domain of ER-alpha and the DNA binding domain of the transcription factor GAL4, and a GAL4-responsive CAT reporter gene. Treatment of cells with estradiol or selenite resulted in a three- to five-fold increase in CAT activity. The effects of selenite on the chimeric receptor were blocked by the antiestrogen, suggesting that selenite activates ER-alpha through an interaction with the hormone binding domain of the receptor. Transfection assays with ER-alpha mutants identified C381, C447, H524, and N532 as interaction sites of selenite with the hormone binding domain.

Molecular and ionic mimicry and the transport of toxic metals

“…Studies in MCF-7 cells have shown that Se, in the form of sodium selenite, binds to the hormone-binding domain of the estrogen receptor resulting in its subsequent activation (Stoica et al, 2000b). Exposure to Se has also been shown to increase the transcription of the progesterone receptor.…”

Aluminium, antiperspirants and breast cancer

“…Replacement of zinc in the zinc finger of ER with either nickel or copper could inhibit the binding of the DNAbinding domain of the ER to the ERE in the DNA [50]. Cadmium [51], arsenite [52], selenite [53], copper, cobalt, nickel, lead, mercury, tin, chromium and vanadate [54] can all interfere with oestradiol binding to the ligand binding domain of the ER and influence oestrogen-regulated gene expression. Furthermore, oestrogenic affects of cadmium have also been demonstrated in vivo in the rodent uterus and mammary gland [55].…”

Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells

“…Inorganic selenite is reported to interact with the ligand binding domain of ERa and activate ERa transcriptional activity (29). To determine whether MSA altered estradiol binding to ERa, whole cell ligand binding assays were done in MCF-7 cells.…”