Badia E, Duchesne M J, Fournier-Bidoz S, Simar-Blanchet A E, Terouanne B, Nicolas J C, Pons M
Centre de Recherche de l'Institut National de la Santé et de la Recherche Médicale, Montpellier, France.
Cancer Res. 1994 Nov 15;54(22):5860-6.
The MVLN cell line was established in our laboratory from MCF-7 cells by stable transfection with the luciferase gene under the control of an estrogen-responsive element from the Xenopus vitellogenin A2 gene. This cell line allowed us to visualize the induction by hydroxytamoxifen of a heterogeneity in the cell population with regard to the expression of the luciferase gene. Treated cells lost their estradiol-inducible luciferase activity, progressively and irreversibly; the luciferase expression of 80% of the cells was irreversibly inactivated by a 12-day hydroxytamoxifen treatment. We showed that this inactivation process was specific for an estrogenic response and was mediated by the estrogen receptor. Tamoxifen itself gave rise to such an inactivation, whereas other compounds belonging to the triphenylethylenic family but differently substituted on the ethylenic carbon and the ICI 164,384 compound were not as efficient. This irreversible inactivation was accompanied by a sharp decrease in the luciferase mRNA level; however, the estrogen receptor function and the cellular transcriptional machinery were 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 heterogeneity in tumor cells throughout the course of patient treatment.
MVLN细胞系是我们实验室从MCF-7细胞通过用来自非洲爪蟾卵黄蛋白原A2基因雌激素反应元件控制下的荧光素酶基因进行稳定转染而建立的。该细胞系使我们能够观察到羟基他莫昔芬诱导细胞群体中荧光素酶基因表达的异质性。经处理的细胞逐渐且不可逆地失去其雌二醇诱导的荧光素酶活性；12天的羟基他莫昔芬处理使80%的细胞的荧光素酶表达不可逆地失活。我们表明这种失活过程对雌激素反应具有特异性，并且由雌激素受体介导。他莫昔芬本身会引起这种失活，而属于三苯乙烯类家族但在乙烯基碳上有不同取代的其他化合物以及ICI 164,384化合物则没有那么有效。这种不可逆的失活伴随着荧光素酶mRNA水平的急剧下降；然而，雌激素受体功能和细胞转录机制不受该处理的影响。尽管这种抗雌激素处理既不影响雌激素依赖的细胞生长，也不不可逆地抑制天然pS2基因的表达，但这些结果强烈表明长期抗雌激素治疗可能在患者治疗过程中导致肿瘤细胞出现一些异质性。
