Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (E1S) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nm and 10 µm, inhibited estrone sulfatase activity by 52 and >98%, respectively. The apparent Km and Vmax for E1S were 4.8 µm and 148 pmol/min/mg for placental and 16.9 µm and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the Ki values for placental and tumor preparations being 14.6 and 32.8 Ém, respectively. A comparison of the metabolism of [3H]E1S and [3H]E13-MTP by human placenta or rat liver revealed that, whereas 50–60% of [3H]E1S was converted to [3H]estrone, <3% of [3H]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

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This study was supported by grants from 3i Research Exploitation Ltd. and Imperial College Exploitation Ltd. B. V. L. P. is a Lister Institute Fellow.

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