Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis.
In estrogen receptor positive human breast cancer cells, anti-estrogens inhibit the mitogenic effect of growth factors in the absence of estrogens. As activator protein-1 (AP-1) activity is one of the first nuclear events following growth factor receptor activation, we studied the effects of estrogens and anti-estrogens on growth factor-induced AP-1 activity using transient transfection of the AP-1-responsive gene (AP-1)4-TK-CAT into MCF7 cells. The growth factor-induced AP-1 response was increased by estradiol and inhibited by anti-estrogens in conditions where growth factor-induced c-fos and c-jun mRNA levels were unchanged by hormone and anti-hormone treatments. The same regulations were obtained when the AP-1 response was directly induced by co-transfection of c-fos and c-jun expression vectors. Co-transfection of the wild-type estrogen receptor HEGO amplified both effects. Inhibition of AP-1 activity by anti-estrogens was unlikely to be explained by the presence of residual estrogens in MCF7 cells. (i) anti-estrogens inhibited AP-1 activity in conditions where they had no effect on basal ERE-mediated activity levels, whereas estradiol was as efficient in stimulating both activities. (ii) The relative efficacy of the two anti-estrogens, OH-tamoxifen and ICI 164,384 in inhibiting these two activities was different; OH-tamoxifen was more efficient in inhibiting ERE-mediated activity, whereas ICI 164,384 was more efficient in trans-repressing AP-1-mediated activity. We conclude that in conditions where c-fos and c-jun syntheses were not affected, the estrogen receptor cooperated with growth factors to stimulate the AP-1 response when activated by estrogens but inhibited AP-1-mediated transcription when occupied by anti-estrogens.
Philips
A
A
University of Montpellier, France.
Chalbos
D
D
Rochefort
H
H
D001943:Breast Neoplasms; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D053284:Polyunsaturated Alkamides; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; C051781:ICI 164384; D015500:Chloramphenicol O-Acetyltransferase; D013937:Thymidine Kinase