The anti-estrogen tamoxifen blocks the stimulatory effects of interleukin-6 on 17β-hydroxysteroid dehydrogenase activity in MCF-7 cells

Abstract

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 17β-estradiol (E2). This is mediated by an increase in reductive 17β-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 mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observation suggest that tamoxifen may reduced 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.