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Action of “pure” antiestrogens in inhibiting estrogen receptor action

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Summary

The mechanism of action of the pure antiestrogens ICI 164384 and ICI 182780 has been investigated. Both antagonists are steroidal antiestrogens with 7α-alkylamide side-chains. The antiestrogens reduce the cellular content of the estrogen receptor by reducing the half-life of the protein. A potential mechanism for this effect is suggested by the observation that the DNA binding activity of receptors which have been over-expressed in cells was inhibitedin vitro. The inhibitory activity of analogues of ICI 164384 with different side chain lengths correlates with their ability to function as pure antiestrogensin vivo. Since the estrogen binding site overlaps with residues involved in dimerisation, the antiestrogens are likely to bind to a similar site and may therefore interfere with receptor dimerisation in the hormone binding domain by means of the 7α side-chain. We propose that the increased turnover of the receptor in the presence of ICI 164384 and ICI 182380 is a consequence of impaired dimerisation of the proteins.

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  1. Imperial Cancer Research Fund, Lincoln's Inn Fields, Laboratory Of Molecular Endocrinology, WC2A 3PX, London, U.K.

    M. G. Parker

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Parker, M.G. Action of “pure” antiestrogens in inhibiting estrogen receptor action. Breast Cancer Res Tr 26, 131–137 (1993). https://doi.org/10.1007/BF00689686

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