Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

Steroid sulfatase: molecular biology, regulation, and inhibition.

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.

Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.

This past summer, United States President Bill Clinton signed into law amendments to the Safe Drinking Water Act and Food Quality Protection Act that include clauses requiring the EPA to develop te...

In Vitro Bioassays for Assessing Estrogenic Substances

Examination of the in Vitro and in VitroEstrogenic Activities of Eight Commercial Phthalate Esters

Importance of estrogen sulfates in breast cancer.

The biological effects and ultrastructural alterations by different estrogen-3-sulfates (E1-3-S and E2-3-S) and estradiol-17-sulfate (E2-17-S) were studied in the MCF-7 mammary cancer cell line in culture. The estrogen-3-sulfates very significantly stimulated the progesterone receptor (PR). The values (in pmoles/mg DNA ± SE) were: control, 0.46 ± 0.09; E1-3-S, 2.24 ± 0.30, and E2-3-S, 2.56 ± 0.45. The value of PR after E2-17-S incubation (0.56 ± 0.24) was similar to the non-treated cells. The PR values obtained by the incubation of unconjugated estrone and estradiol were: 2.63 ± 0.45 and 2.27 ± 0.36, respectively. Analysis of the unconjugated estrogens in the medium indicated significant hydrolysis of estrogen-3-sulfates but not of E2-17-S. Using [3H]-E1-3-S, an important transformation was observed inside the cells, a great part being converted to estradiol (>60% in the nuclear fraction). Electron microscopic examination indicated alterations in the secretory system after incubation with estrogen-3-sulfates similar to those obtained with unconjugated estradiol. The effect provoked by E2-17-S was significantly less than for the other sulfates.

C. Gelly

Papers

Estrogen sulfates: biological and ultrastructural responses and metabolism in MCF-7 human breast cancer cells.