HYDROXYTAMOXIFEN INDUCES A RAPID AND IRREVERSIBLE INACTIVATION OF AN ESTROGENIC RESPONSE IN AN MCF-7-DERIVED CELL-LINE

The MLVN cell line was established in our laboratory from MCF-7 cells by stable transfection with the luciferase gene under the control of a n estrogen-responsive element from the Xenopus vitellogenin A2 gene. T his cell line allowed us to visualize the induction by hydroxytamoxife n of a heterogeneity in the cell population with regard to the express ion of the luciferase gene. Treated cells lost their estradiol-inducib le luciferase activity, progressively and irreversibly; the luciferase expression of 80% of the cells was irreversibly inactivated by a 12-d ay hydroxytamoxifen treatment. We showed that this inactivation proces s was specific for an estrogenic response and was mediated by the estr ogen receptor. Tamoxifen itself gave rise to such an inactivation, whe reas other compounds belonging to the triphenylethylenic family but di fferently substituted on the ethylenic carbon and the ICI 164,384 comp ound were not as efficient. This irreversible inactivation was accompa nied by a sharp decrease in the luciferase mRNA level; however, the es trogen receptor function and the cellular transcriptional machinery we re not affected by the treatment. Although this antiestrogen treatment neither affected the estrogen-dependent cell growth nor irreversibly inhibited the expression of the natural pS2 gene, these results highly suggest that long-term antiestrogen therapy may lead to some heteroge neity in tumor cells throughout the course of patient treatment.