THE ANTIESTROGEN 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 t he cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF- 7 human breast carcinoma cells to convert estrone (E1) to the biologic ally more active 17beta-estradiol (E2). This is mediated by an increas e in reductive 17beta-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 reduc tive 17-HSD activity (E1 --> E2), but are already maximally inhibitory for the oxidative reaction (E2 --> E1). Increasing intracellular conc entrations of E2, however, stimulated the reductive 17-HSD in a dose-d ependent manner. IL-6 stimulated the reductive pathway and was synergi stic with E2. IL-6 is most likely acting through an E2-dependent mecha nism, since tamoxifen completely reversed the effects of E2 and IL-6 s eparately and in combination. These observations suggest that tamoxife n may reduce intratissular levels of E2 by directly increasing oxidati ve 17-HSD activity and by blocking the actions of paracrine factors su ch as IL-6 which increase reductive 17-HSD activity.