Dehydroepiandrosterone stimulates proliferation and gene expression in MCF-7 cells after conversion to estradiol.
Dehydroepiandrosterone (DHEA) is a mitogen for estrogen-dependent MCF-7 breast cancer cells. Our aims were to determine whether DHEA required conversion to estrogens in order to stimulate cell proliferation and estrogen-dependent gene expression. After incubation of cells with 100 nM DHEA for 4 days, estradiol was present in the medium at a concentration of approximately 200 pM. Other compounds identified were testosterone ( approximately 300 pM) and estrone. Significant stimulation of cell proliferation by 1 nM estradiol and 100 nM DHEA was observed after 38 h and 4 days of incubation, respectively, indicating the necessity of DHEA conversion. DHEA doses > or = 10 nM induced estrogen-dependent reporter gene expression in MCF-7 cells transfected with a luciferase reporter gene under the control of the estrogen response element. DHEA-dependent stimulation of proliferation and luciferase induction could be inhibited by the anti-estrogens ICI182,780 and tamoxifen, respectively, and by the aromatase inhibitor 4-hydroxyandrostenedione. An androgenic effect of DHEA on proliferation and gene expression of MCF-7 cells was not observed. We conclude that conversion of DHEA to estrogens, particularly estradiol, is required to exert a mitogenic response.
Research Group 'Hormones and Signal Transduction', Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
M
M
Schmitt
K
K
Klinga
B
B
Schnarr
R
R
Morfin
D
D
Mayer
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002855:Chromatography, Thin Layer; D003687:Dehydroepiandrosterone / Q000378:metabolism* / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007118:Immunoassay; D008934:Mitogens / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D008934:Mitogens; D013196:Dihydrotestosterone; D013629:Tamoxifen; D000077267:Fulvestrant; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D004958:Estradiol; D003907:Dexamethasone; D001141:Aromatase; C014594:formestane