[The elucidation of the antiestrogen and antitumoral mechanisms of tamoxifen].

Our contribution to elucidation of the mechanism of action of tamoxifen can be summarized as follows: (i) hydroxylated metabolites of tamoxifen (especially 4-hydroxytamoxifen), with high affinity for the oestrogen receptor are more potent antioestrogen and antitumoral agents than tamoxifen; they might play an important role in the in vivo antioestrogenic and antitumoral activities of tamoxifen; (ii) the activity of tamoxifen and derivatives in vitro is closely related to their affinity for the receptor; (iii) certain oestrogen receptor properties (dissociation kinetics, immunoreactivity, sensitivity to specific reagents) vary according to whether oestrogen or antioestrogen is bound to the receptor. These variations probably result from different "positioning" of oestrogen and antioestrogen at the receptor hormone-binding site. They indicate that antioestrogens may induce altered conformation and probably defective activation of the oestrogen receptor. This could be the cause of the antioestrogenic and antitumoral effects of these compounds. It is now widely accepted that the oestrogen receptor is the major if not the only mediator of antioestrogenic and antitumoral effects of triphenylethylene antioestrogens in mammary tumor cells. These compounds efficiently promote dimerization and binding of the receptor to target DNA. Their relative lack of oestrogenic activity could result from (i) their inability to activate the transactivating function of the receptor involved in transcription regulation of certain oestrogen-target genes; (ii) the accumulation of anomalous receptor forms; and (iii) deficient phosphorylation state of the receptor. Besides their conventional antioestrogenic activity, antioestrogens could also exert action which antagonizes the "oestrogenic" effects of various growth factors in cells expressing the oestrogen receptor. This action could cause antitumoral effects in the absence of oestrogens. Two main mechanisms could account for the resistance to antioestrogens in sensitive mammary tumor cells: (i) loss of oestrogen-dependent expression of growth factors, and (ii) change in the dominant activity of antioestrogens (antagonist-->agonist) in the cells, whose proliferation would be then stimulated by antioestrogens. New steroidal "pure" antioestrogens have been developed. These compounds seem capable of promoting dimerization and then receptor binding to target DNA. However, they could induce rapid and marked decreases in the oestrogen receptor concentration in cells, which might account for their antioestrogenic activity. These compounds are able to antagonize the oestrogenic effects of triphenylethylene antioestrogens and especially the growth of resistant mammary tumors stimulated by the latter compounds. They are of great interest for the future treatment of mammary breast tumors expressing the oestrogen receptor.