MULTIPLE STEROID METABOLIC PATHWAYS IN ZR-75-1 HUMAN BREAST-CANCER CELLS

In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37-degrees-C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3-beta, 17-beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steriods were extracted, separated into free steriods, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5-alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5-alpha-reductase as well as 3-alpha-and 3-beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17-beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.