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FRA-1 Expression Level Modulates Regulation of Activator Protein-1 Activity by Estradiol in Breast Cancer Cells

Institut National de la Santé et de la Recherche Médicale Hormones and Cancer (U 148), and Université de Montpellier I 34090 Montpellier, France

We compared the effect of estradiol on activator protein-1 (AP-1) activity in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast cancer cell lines transiently transfected with the AP-1-responsive reporter plasmid AP-1-TK-CAT and an ER expression vector. While estradiol increased AP-1 activity in the ER+ cell lines MCF7, ZR75.1, and T47D, it decreased (MDA-MB231 and BT20 cells) or had no significant effect (MDA-MB435 cells) on AP-1-mediated transcription in ER- cells. Estradiol also inhibited AP-1 activity in ER-MDA-MB231 cells stably transfected with ER and in which ER levels are close to those found in MCF7. Use of ER mutant expression vectors demonstrated that the DNA-binding domain of ER was needed for stimulation or inhibition of AP-1 activity by estradiol but suggested that ER binding to estrogen-responsive elements was not required for these effects. Changes in regulation paralleled quantitative and qualitative changes in protein binding to AP-1 sites, as demonstrated by gel shift assay: protein binding was greater and DNA/protein complexes migrated faster for ER- than for ER+ cells. In fact, by Northern blot, a high level of Fra-1 mRNA was found in BT20 and MDA-MB231 cells as compared with ER+ cells, and MDA-MB435 cells showed an intermediary level of expression. The differential expression of Fra-1 in MCF7 and MDA-MB231 cells was confirmed at the protein level by supershift experiments. In addition, overexpression of Fra-1 in MCF7 cells decreased the positive effect of estradiol while inhibition of Fra-1 expression in MDA-MB231 cells, by transient transfection of the Fra-1 antisense expression vector, abolished the negative effect of the hormone. In conclusion, we demonstrated that ER- breast cancer cell lines differ from ER+ cells by a high level of AP-1 DNA-binding activity due, at least in part, to high Fra-1 constitutive expression. High Fra-1 concentration is crucial for the negative regulation of AP-1 activity by estradiol and thus may take part in estradiol-induced inhibition of cell proliferation in ER- breast cancer cells transfected with ER expression construct.

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