INHIBITION OF ESTRONE SULFATASE ENZYME IN HUMAN PLACENTA AND HUMAN BREAST-CARCINOMA

Estrone sulfatase is an important mechanism of local synthesis of biologically active estrogens in human breast cancer. The human placental microsome and breast carcinoma mitochondrial/microsomal estrone sulfatase activity were characterized and inhibition studies performed. The K(m) of the placental tissue enzyme was 6.83-mu-M, V(max) 0.015 nmol/min/mg, and for the breast carcinoma tissue K(m) was 8.91-mu-M and V(max) 0.022 nmol/min/mg. Danazol produced a significant inhibition of estrone sulfatase (20% with 50-mu-M danazol). No significant inhibition was seen in the presence of aminoglutethimide, rogletimide, tamoxifen, 4-hydroxyandrostenedione, stilboestrol, or any metabolites of danazol or tamoxifen. Studies with synthetic and naturally occurring steroids demonstrated that the presence of a sulfate group at the 3 position to be the most important factor in determining inhibition, and the most potent inhibitor was 5-alpha-androstene-3-beta,17-beta-diol-3-sulfate (K(i) of 2.0-mu-M). The naturally occurring 3-sulfated steroids all demonstrated competitive inhibition. These studies could form the basis for the design of a potent estrone sulfatase inhibitor which would have potential therapeutic activity in the management of breast cancer.