[Modulation of cellular response expression during prolonged treatment with antiestrogens]

The effects of a prolonged antiestrogen treatment on two estrogen-dependent responses and an AP-1 response were studied on two cell lines derived from MCF-7 cells. 1) Hydroxytamoxifen specifically provoked an irreversible inactivation of a chimeric estrogen-dependent gene expression in less than 30 days. This process was estrogen receptor mediated and led to a cellular heterogeneity that was induced by the treatment and was not due to a cell selection process. A similar heterogeneity was also observed for the progesterone receptor expression but after a longer treatment time. The mechanism underlying this phenomenon is currently investigated. 2) After a four day treatment of cells with an antiestrogen, the phorbol ester inducible expression of a chimeric AP-1 response was stimulated by a factor 3-4. This stimulation was antiestrogen dose-dependent and suppressed by the presence of estradiol, which strongly suggested that estrogen receptor was involved. This was confirmed by the fact that the phenomenon was not observed in a cell line devoid of estrogen receptor. This result suggests a yet unknown mechanism by which an antiestrogen could have an agonistic property allowing hormone independence to appear. Both these phenomena show that new activities of antiestrogens may be evidenced after prolonged treatments with unexpected consequences on endocrine therapy.