Human
breast cancer tissue contains
enzymes (
estrone sulfatase, 17beta-
hydroxysteroid dehydrogenase,
aromatase) involved in the last steps of
estradiol (E(2)) formation. In this tissue, E(2) can be synthesized by two main pathways: (1)
sulfatase-transforms
estrogen sulfates into bioactive E(2), and the (2)
aromatase-converts
androgens into
estrogens. Quantitative assessment of E(2) formation in human
breast tumors indicates that metabolism of
estrone sulfate (E(1)S) via the
sulfatase pathway produces 100-500 times more E(2) than
androgen aromatization. In the present study, we demonstrated in T-47D and MCF-7 human
breast cancer cells that
norelgestromin (NGMN) (a metabolite of
norgestimate) is a potent inhibitory agent of the
estrone sulfatase activity. After 24h incubation of physiological concentrations of E(1)S (5 x 10(-9)mol/l) the inhibitory effect of NGMN at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 43+/-7, 74+/-4 and 97+/-2%, respectively, in T-47D cells; 25+/-4, 57+/-5 and 96+/-2% respectively, in MCF-7 cells. Comparative studies using
medroxyprogesterone acetate (MPA) showed that this
progestin also has an inhibitory effect on
sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 31+/-5, 47+/-3 and 61+/-3%, respectively, for T-47D cells; 6+/-3, 20+/-3 and 63+/-4%, respectively, for MCF-7 cells. In conclusion, the present data show that NGMN is a very potent inhibitory agent for
sulfatase activity in the
hormone-dependent
breast cancer cells, resulting in decreased tissue concentration of E(2). The clinical significance of this finding remains to be elucidated.