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Antiestrogenic properties of keoxifene,trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells

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Abstract

The agonistic/antagonistic properties of two non-steroidal antiestrogens, namelytrans-4-monohydroxy-tamoxifen (OH-TAM) and keoxifene (LY156758), and the new steroidal antiestrogen ICI164384, a 7β-alkylamide derivative of estradiol (E2), were assessed by measuring their effect on the proliferation of ZR·75-1 cells, an estrogen-responsive human breast cancer cell line. While subnanomolar concentrations of both OH-TAM and LY156758 had significant estrogenic stimulatory activity on cell growth in the absence of estrogens and higher concentrations were inhibitory, ICI164384 behaved exclusively as a growth inhibitor and more potently so than the two other compounds. The three antiestrogens had similar potency to inhibit the mitogenic effect of E2 and at 300 nM, all antiproliferative effects were completely reversible by the estrogen. ICI164384 was a weaker competitor of3H-labeled E2 or R2858 (moxestrol) uptake in intact ZR-75-1 cells in a 1-hour assay, partly because of a slower intracellular access to estrogen specific binding sites. Moreover, ICI164384 interacted in a rapidly (~ 6 h) reversible manner with estrogen-specific binding sites, while the non-steroidal antiestrogens induced a longer-acting (> 24 h) down-regulation of specific [3H]R2858 uptake. The present data indicate that, among the antiestrogens studied, ICI164384 is the only compound acting as a pure antiestrogen in ZR-75-1 breast cancer cells, while LY156758 and OH-TAM behave as antiestrogens endowed with partial agonistic activity in this system.

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Authors and Affiliations

  1. MRC Group in Molecular Endocrinology, CHUL Research Center, Laval University Medical Center, 2705 Boulevard Laurier, G1V 4G2, Sainte-Foy, Quebec, Canada

    Richard Poulin, Yves Merand, Donald Poirier, Charles Levesque, Jean-Marc Dufour & Fernand Labrie

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  1. Richard Poulin
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  2. Yves Merand
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  3. Donald Poirier
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  4. Charles Levesque
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  5. Jean-Marc Dufour
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  6. Fernand Labrie
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Poulin, R., Merand, Y., Poirier, D. et al. Antiestrogenic properties of keoxifene,trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast Cancer Res Tr 14, 65–76 (1989). https://doi.org/10.1007/BF01805977

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