title: Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells.
abstract: Tamoxifen is used widely in the treatment of endocrine-responsive breast cancers in humans. Studies were undertaken to examine the biological character (estrogenic-antiestrogenic properties) and estrogen receptor (ER) interaction of the cis- and trans-isomers of tamoxifen and hydroxytamoxifen in MCF-7 human breast cancer cells. For each compound, the following parameters were monitored: affinity for ER and effects on cellular ER levels; stimulation-inhibition of cell growth, plasminogen activator activity, and cellular progesterone receptor levels; and isomer interconversion and metabolism in vitro. The relative binding affinities of the compounds cis-tamoxifen, trans-tamoxifen, cis-hydroxytamoxifen, and trans-hydroxytamoxifen for cytosol ER were 0.3, 2.5, 1.8, and 310%, respectively, in which the affinity of estradiol is considered 100%. cis-Tamoxifen behaved as a weak estrogen agonist in all assays, while trans-tamoxifen was an effective estrogen antagonist. cis-Tamoxifen behaved like estradiol in stimulating MCF-7 cell growth and increasing plasminogen activator activity and cellular progesterone receptor content, although very much higher concentrations of cis-tamoxifen (10(-6) M) were needed to achieve the levels of stimulation observed with 10(-10) M estradiol. trans-Tamoxifen and trans-hydroxytamoxifen suppressed cell growth, inhibited plasminogen activator activity of control cells, and suppressed estradiol-stimulation of plasminogen activator activity, and they evoked minimal increases in cellular progesterone receptor levels. trans-Hydroxytamoxifen had a 100-fold increased affinity for ER and was approximately 100-times more potent than was trans-tamoxifen in suppressing cell growth and plasminogen activator activity. cis-Hydroxytamoxifen behaved as an estrogen antagonist, suppressing cell growth and plasminogen activator activity, and it elicited submaximal increases in progesterone receptor levels. This apparently paradoxical behavior of cis-hydroxytamoxifen was shown to be due to the fact that the cis- and trans-hydroxytamoxifens readily undergo isomeric interconversion upon exposure to our cell culture conditions, resulting in substantial accumulation of the higher-affinity trans-hydroxytamoxifen in the nuclear ER fraction of cells. In contrast to the facile interconversion of the hydroxytamoxifen isomers, there is no metabolism or interconversion of the parent compounds cis- and trans-tamoxifen in vitro. Hence, by the criteria we have used, the biological characters of trans-tamoxifen and trans-hydroxytamoxifen are similar, the major difference being the approximately 100-fold enhanced potency of the hydroxylated form. In contrast, cis-t
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010960:Plasminogen Activators / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C016601:afimoxifene; D010960:Plasminogen Activators