BIOACTIVITIES, ESTROGEN-RECEPTOR INTERACTIONS, AND PLASMINOGEN ACTIVATOR-INDUCING ACTIVITIES OF TAMOXIFEN AND HYDROXYTAMOXIFEN ISOMERS IN MCF-7 HUMAN-BREAST CANCER-CELLS

Google Scholar
  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (1) , 112-119
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 behaves 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 .apprx. 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 the 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. The biological characters of trans-tamoxifen and trans-hydroxytamoxifen are similar, the major difference being the .apprx. 100-fold enhanced potency of the hydroxylated form. cis-Tamoxifen is an estrogen with a biopotency roughly proportional to its ER binding affinity. The apparent estrogen-antagonistic character of cis-hydroxytamoxifen appears attributable to isomerization to trans-hydroxytamoxifen in vitro. With all tamoxifen isomers, there wasa good correlation between suppression or stimulation of plasminogen activator activity and suppression or stimulation of cell growth, suggesting that cell-associated plasminogen activator activity may serve as a good marker for estrogen action in breast cancer cells.