Inhibition of estrone sulfatase enzyme in human placenta and human breast carcinoma

Abstract

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 μM, V max 0.015 nmol/min/mg, and for the breast carcinoma tissue K m was 8.91 μM and V max 0.022 nmol/min/mg. Danazol produced a significant inhibition of estrone sulfatase (20% with 50 μM 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 occuring 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 5α-androstene-3β, 17β-diol-3-sulfate ( K i of 2.0 μM). The naturally occuring 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.