The anti-estrogen tamoxifen blocks the stimulatory effects of interleukin-6 on 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells.
Previous studies have revealed that human breast fibroblasts secrete the cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF-7 human breast carcinoma cells to convert estrone (E1) to the biologically more active 17 beta-estradiol (E2). This is mediated by an increase in reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity. In the studies described here, we have extended our observations using the anti-estrogen, tamoxifen, to demonstrate that in a steady state, endogenous intracellular concentrations of E2 have no effects on reductive 17-HSD activity (E1-->E2), but are already maximally inhibitory for the oxidative reaction (E2-->E1). Increasing intracellular concentrations of E2, however, stimulated the reductive 17-HSD in a dose-dependent manner. IL-6 stimulated the reductive pathway and was synergistic with E2. IL-6 is most likely acting through an E2-dependent mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observations suggest that tamoxifen may reduce intratissular levels of E2 by directly increasing oxidative 17-HSD activity and by blocking the actions of paracrine factors such as IL-6 which increase reductive 17-HSD activity.
Speirs
V
V
Department of Medicine, University of Liverpool, England.
Adams
E F
EF
White
M C
MC
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D015067:17-Hydroxysteroid Dehydrogenases; D004958:Estradiol; D015850:Interleukin-6; D013629:Tamoxifen; D000093242:Interleukin-6 Inhibitors