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Departments of Physiology and Biophysics [B.S.K., M.J.N., R.L.E.] and Biochemistry [S.W.P., W.F.M.], University of Illinois, and University of Illinois College of Medicine, Urbana, Illinois 61801
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 10-10M 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-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 was a 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.
1 Supported by NIH Grants CA 18119 and CA 31870 from the National Cancer Institute. To whom requests for reprints should be addressed, at Department of Physiology and Biophysics, 524 Burrill Hall, University of Illinois, 407 South Goodwin Avenue, Urbana, Ill. 61801.
2 Supported by NIH Grant CA 25633 from the National Cancer Institute.
Received 5/11/83. Accepted 9/28/83.
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