Effects of fadrozole and leuprorelin acetate on aromatase activity and cell proliferation in a human breast cancer cell line (SK-BR-3)

Background. In recent years, aromatase inhibitors have been used to treat hormone-dependent breast cancer in postmenopausal women. Although gonadotropin-releasing hormone (GnRH) agonists inhibit the growth of breast cancers by estrogen deprivation, it is not known whether GnRH agonists have a direct effect on breast cancer cells. In the present study, we examined the direct effect of a GnRH agonist (leuprorelin acetate) on aromatase activity in a human breast cancer cell line, SK-BR-3. We also studied the synergistic effect of fadrozole (an aromatase inhibitor) and leuprorelin acetate on aromatase activity and cell proliferation in SK-BR-3 cells. Methods. Aromatase activity was determined by measuring [³H] water released upon the conversion of [1β-³H] androstenedione to estrone. Cell proliferation was estimated by determining the incorporation of 5-bromo-2′-deoxyuridine in cellular DNA (cell proliferation assay system). Results. Aromatase activity in SK-BR-3 was inhibited by fadrozole. In addition, SK-BR-3 aromatase activity was inhibited by leuprorelin acetate. Stimulation of cell proliferation by estradiol (10 nM) and testosterone (20 nM) was almost completely inhibited by the addition of an estrogen receptor antagonist, ICI 182780 (10 nM), and fadrozole (1 nM). When both these compounds were added, the most potent inhibition of aromatase activity (fadrozole, 0.1 nM; leuprorelin acetate, 1 nM) and cell proliferation (fadrozole, 10 nM; leuprorelin acetate, 100 nM) was observed. Conclusions. These results lead us to the conclusion that combination therapy with an aromatase inhibitor and a GnRH agonist may provide a new treatment for both pre- and postmenopausal patients with hormone-dependent breast cancer. Received: October 26, 1999 / Accepted: January 26, 2000