Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We determined the effects of epidermal growth factor, insulin-like-growth-factor-1 and estradiol on the anchorage independent growth of the estrogen receptor positive human breast cancer cell lines MCF7 and T-47D. In serum free conditions growth factors but not estrogen induced a dose dependent stimulation of growth in both cell lines. The ability of estrogen to induce colony formation of early passage MCF7 cells (less than 100) was strictly correlated to the concentration of sulfatase and charcoal treated calf serum (CCS) with a maximal effect at a concentration of 5% CCS and 10 nM estradiol. CCS alone had no stimulatory effect on the anchorage independent growth of early passage MCF7 cells, but increased colony formation in late passage (greater than 1000) MCF7 and T-47D cells. The growth of late passage MCF7 cells was inhibited by antiestrogen. Thus, the presence of serum components is necessary for the effect of estrogen but not for the effects of growth factors on the anchorage independent growth of estrogen receptor positive human breast cancer cell lines; after a prolonged period of tissue culture serum components switch their function from indirectly modulating estrogen effects to directly stimulating growth in the absence of estrogen.
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PMID:Tissue culture conditions determine the effects of estrogen and growth factors on the anchorage independent growth of human breast cancer cell lines. 195 6

The metabolism of 17 beta-estradiol in both estrogen receptor positive and negative human breast cancer cell lines has been compared. Initial experiments in which confluent cells were exposed to 1 nM [3H]17 beta-estradiol for 24 h, revealed that the main metabolites formed by estrogen receptor positive MCF-7 and ZR-75-1 cells were 17 beta-estradiol-3-sulfate (together with lesser amounts of estrone sulfate) and estrone. In estrogen receptor negative cell lines, production of estrogen sulfates was either significantly lower (MDA-MB-231 cells) than receptor positive cells, or failed to be produced at all (MDA-MB-330 cells). In both these receptor negative cell lines, production of estrone was significantly higher than in receptor positive cells. Accumulation of estrogen sulfates resulted from attainment of a steady state between synthesis catalysed by estrogen sulfotransferase and degradation catalysed by estrogen sulfatase. The former was present in the cytosol and showed a very high affinity for 17 beta-estradiol and estrone (low nM range). Complex initial velocity versus estrogen substrate curves were obtained with enzyme purified 106-fold by affinity chromatography. Such curves were consistent with a rate equation of degree 3 or 4 and suggest the presence of cooperatively linked dependent binding sites.
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PMID:Metabolic fate of estradiol in human mammary cancer cells in culture: estrogen sulfate formation and cooperativity exhibited by estrogen sulfotransferase. 320 95

Estrone and estradiol concentrations in breast tumor tissue are an order of magnitude higher than circulating plasma levels in postmenopausal women with breast cancer. Local production of estrogen in the neoplastic tissue is one of several possible explanations for this plasma/tissue gradient. This study evaluated breast tumor estrogen production via the estrone sulfate to estrone (sulfatase) pathway and compared this with the androstenedione to estrone (aromatase) system in human and rodent mammary tumors. Estrogen production from estrone sulfate was related linearly with time and tissue concentrations, exhibited an apparent Km of 20 microM, and produced a linear Eadie-Hofstee kinetic plot consistent with a single class of enzymatic sites. Measurement of sulfatase in 35 human breast tumors using enzyme saturating conditions revealed estrone production ranging from 0.8-125 mumol/g protein . h. The corresponding range in host mammary tumors was 3.5-7.1 mumol/g protein . h. In human breast tumors, sulfatase activity did not correlate with the levels of estrogen receptor or progesterone receptor. Comparison of sulfatase with aromatase activity in human tumors at physiological levels of substrate revealed estrone formation via sulfatase of 2.8 pmol estrone produced/g protein . h, while aromatase produced only 0.27 pmol/g protein . h. In rat mammary tumors, sulfatase activity was similar to that in human tumors, whereas aromatase activity could not be detected, even with a highly sensitive assay. Thus, estrone sulfatase appears to be the enzyme primarily responsible for intratissue estrone production in hormone-dependent breast carcinomas.
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PMID:In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. 672 22

Estradiol levels in breast tumors from post-menopausal women are similar to those in pre-menopausal women even though plasma estrogens are much lower after the menopause. In situ estrogen production by the tumor provides a potential means of maintaining high estradiol levels in post-menopausal breast cancer tissue. The estrone sulfatase pathway has been proposed as the mediator of in situ estrogen production. A number of studies suggest that estrone sulfate may be converted into estradiol in breast tumors via the catalytic activity of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase. However, these studies used pharmacologic levels of estrogen sulfates and have not shown that physiologic levels can support biologic effects. Accordingly, the present study examined the dose relationship of estrone sulfate to a variety of biologic endpoints in MCF-7 breast cancer cells in culture. These cells converted physiologic concentrations of estrone sulfate to quantities of free estradiol capable of stimulating cell growth. Under these conditions, the nuclear steroids observed were free estrone and estradiol. Increase in cell number after 6 days of exposure to steroid required 100 nM estrone sulfate. However, S-phase, a more sensitive measure of cell proliferation, was stimulated by 0.1 nM estrone sulfate, a clearly physiologic concentration. Stimulation of estrogen-dependent protein markers such as pS2 and progesterone receptor required much higher concentrations of estrone sulfate. These effects were mediated through the estrogen receptor since the pure anti-estrogen, ICI 164384, blocked all effects produced by estrone sulfate. While it has been suggested that anti-estrogens may partly exert their effects by inhibition of sulfatase and 17 beta-hydroxysteroid dehydrogenase, this did not occur under our experimental conditions. These data provide evidence of the relevance of the estrone sulfatase pathway since biologic effects can be demonstrated in response to physiologic concentrations of estrone sulfate.
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PMID:Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF-7 cell cultures. 847 38

Steroid sulfatase (STS) hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate. In the present study, we have measured STS mRNA levels in 97 breast cancers by reverse transcription-PCR using a fluorescent primer in the presence of an internal standard RNA and evaluated its association with disease-free and overall survival. The median value was 728.0 amol/ng RNA (range, 0-11,778 amol/ng RNA). Levels were significantly higher in tumors demonstrating lymph node metastasis than in those without nodal involvement (P = 0.033) and in patients who experienced a recurrence during the follow-up period (mean, 40.8 months; median, 39 months) compared with those with no evidence of further disease (mean, 49.2 months; median, 48 months; P = 0.029). No significant associations were found between STS mRNA expression and age, menopausal status, tumor size, histological grade, estrogen receptor status, or postoperative adjuvant therapy. High levels of STS mRNA proved to be a significant predictor of reduced relapse-free survival as a continuous variable (log STS mRNA; P = 0.028). As a dichotomous variable with an optimized cutoff point of 1,240 amol/ng RNA, expression was also associated with a significantly shorter relapse-free survival rate (P = 0.002), but no significant correlation was found between the STS mRNA level and overall survival. Expression was found to be an independent factor for predicting relapse-free survival on multivariate analysis. The results thus support a putative role of STS in breast cancer growth and metastasis.
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PMID:Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. 992 50

To develop inhibitors of steroid sulfatase without residual estrogenic activity, we have designed a series of estradiol (E2) derivatives bearing an alkan (or alkyn) amide side chain at position 17alpha. A hydrophobic alkyl group was selected from our previous study where 17alpha-octyl-E2 was found to inhibit strongly the steroid-sulfatase activity. Furthermore, it is known that an alkylamide side chain blocks the estrogen-receptor activation. Starting from ethynylestradiol, the chemical synthesis of target compounds was short and efficient with overall yields of 22-42% (3 or 4 steps). Among these compounds, N-octyl,N-methyl-3-(3',17'beta-dihydroxy-1',3',5'(10')-estratrien- 17'alpha-yl)-propanamide (15) was the most potent inhibitor, with an IC50 value of 0.08 microM for the transformation of estrone sulfate (E1S) to estrone (E1) by homogenated JEG-3 cells. N-butyl, N-hexyl, and N,N-dioctyl propanamide derivatives of E2 (IC50 values of 6.4, 2.8, and >20 microM, respectively) were less potent inhibitors than N-octyl analog 15. Furthermore, the unsaturated propynamide analog of 15 gave lower inhibition (four times) than the saturated compound. Compound 15 is also about 100-fold more effective in interacting with the enzyme than substrate E1S itself. The ability of target compounds to bind the estrogen receptor, to stimulate the proliferation of estrogen-sensitive ZR-75-1 cells, or to inhibit the E2-stimulation of ZR-75-1 cells was also evaluated. Although a mixed estrogenic/anti-estrogenic activity was obtained for tested compounds at 1 microM, no estrogenic activity was observed at 0.03 microM for 15. In conclusion, a promising inhibitor of steroid-sulfatase activity was obtained by introducing a hydrophobic octyl group in a 17alpha-propanamide side chain of E2, but further structure-activity relationships (SAR) studies are necessary to minimize the residual estrogenic activity.
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PMID:17Alpha-alkan (or alkyn) amide derivatives of estradiol as inhibitors of steroid-sulfatase activity. 1057 17

More than two-thirds of breast cancers occur in post-menopausal women, and depend on the estrogens for their proliferation and survival. For the treatment of estrogen-dependent breast cancers, two major treatment options are now available. One is selective estrogen receptor modulator (SERM) such as Tamoxifen and another is aromatase inhibitor such as Anastrozole, Letrozole and Exemestane, which reduce local in situ formation of estrogens. Although these therapies are clinically active for advanced and early breast cancers, de novo and/or acquired resistance to SERM and/or aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of estrogens in the breast tumors is more important than circulating estrogen in plasma for the growth and survival of estrogen-dependent breast cancer in post-menopausal women. The rationale for the importance of local formation of estrogens is based on the following evidences. Estradiol (E2) levels in breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in breast tumors of post-menopausal women are 10-40 times higher than serum level. Biosynthesis of estrogens in breast tumors tissues occurs via two major different routes, one is aromatase pathway and another is steroid-sulfatase (STS) pathway. Whereas many studies has been reported about aromatase inhibitor and its clinical trial results in breast cancer patients, limited information are available regarding to other estrogen regulating enzymes including STS, its role in breast tumors and STS inhibitors. STS is the enzyme that hydrolyses estrone 3-sulfate (E1S) and dehydroepiandrosterone-sulfate (DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of estrogen-dependent breast tumors. It has been well known that E1S level are much higher than E2 level both in plasma and tumor of post-menopausal patients. Recent reports show that more than 80% of breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in breast cancer. Taking these findings into consideration, local formation of estrogens could be partially synthesized from large amount of E1S by STS, which exist in breast cancer. On the other hand, aromatase localizes in stroma and adipocyte surrounding breast cancer. Furthermore, since estrogen formation from E1S and DHEA-S (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of estrogen-dependent tumor post-SERM and/or aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal breast cancer patients is reviewed as well as STS inhibitor.
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PMID:Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients. 1462 44

There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E2) from circulating precursors. Two principal pathways are implicated in the final steps of E2 formation in breast cancer tissue: the 'aromatase pathway' that transforms androgens into estrogens and the 'sulfatase pathway' that converts estrone sulfate (E1S) into estrone (E1) via estrone sulfatase. The final step is the conversion of weak E1 to potent biologically active E2 via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. One of the possible means of blocking E2 effects in breast cancer is to use anti-estrogens, which act by binding to the estrogen receptor (ER). Another option is to block E2 using anti-enzymes (anti-sulfatase, anti-aromatase, or anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD). Various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, 17-deacetyl norgestimate, dydrogesterone and its 20-dihydro derivative), as well as tibolone and its metabolites, have been shown to inhibit estrone sulfatase and 17beta-hydroxysteroid dehydrogenase. Some progestins and tibolone can also stimulate sulfotransferase activity. These various progestins may therefore provide a new option for the treatment of breast cancer.
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PMID:Differential effects of progestins on breast tissue enzymes. 1467 Jun 45

Estrogens are essential for bone mass accrual but their role before sexual maturation has remained elusive. Using in situ hybridization and immunohistochemistry, we investigated the expression of both estrogen receptor (ER) alpha and beta mRNA and protein as well as several mRNAs coding for enzymes involved in sex steroid metabolism (aromatase, type I and II 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), steroid sulfatase (STS) and type I 5 alpha-reductase) on sections of tibial metaphyses before (1- and 4-week-old), during (7-week-old) and after (16-week-old) sexual maturation in female and male rats. ER alpha and ER beta mRNA and protein were detected in metaphyseal bone in lining cells, osteoblasts, osteoclasts and some osteocytes with no apparent differences in expression during development or between the sexes. In contrast, aromatase, type I and II 17 beta-HSD and type I 5 alpha-reductase mRNAs were first detected in osteoblasts, osteoclasts and occasionally in osteocytes from sexual maturation (7-week-old rat) and onwards. Only STS was present before sexual maturation. To study the significance of ER alpha and beta expression in bone before sexual maturation when circulating sex steroid levels are low, 26-day-old female and male rats underwent gonadectomy or 17 beta-estradiol (E(2)) supplementation (0.5 mg/21 days) during 3 weeks. Following gonadectomy, trabecular bone volume (TBV) was lower in males (P=0.03) and there was a trend towards reduction in females (P=0.057). E(2) supplementation increased tibial TBV compared with controls in both genders as assessed by Masson-Goldner staining. These data suggest that the presence of ERs in bone cells before sex maturation might be of significance for bone mass accrual. Furthermore, based on the mRNA expression of the crucial enzymes aromatase and type I 17 beta-HSD, we suggest that bone cells in the tibial metaphysis acquire the intrinsic capacity to metabolize sex steroids from sexual maturation onwards. This process may contribute to the beneficial effects of estrogen on bone mass accrual, possibly by intracrinology.
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PMID:Expression of estrogen receptors and enzymes involved in sex steroid metabolism in the rat tibia during sexual maturation. 1501

Effluents from wastewater treatment works (WwTWs) contain estrogenic contaminants that can cause feminised responses in fish. In order to assess the identity of estrogenic contaminants taken up by fish exposed to effluents, an analytical method was developed to detect estrogenic substances in fish bile, where many xenobiotics are excreted and concentrated. Estrogenic metabolites in bile were deconjugated using enzymatic hydrolysis and the estrogenic activity was determined using a yeast estrogen receptor transcription screen (YES). Hydrolysed samples were concentrated by solid-phase extraction (SPE) prior to fractionation by reversed-phase high-performance liquid chromatography (HPLC). Active HPLC fractions were detected by YES assay and analysed by gas chromatography-mass spectrometry (GC-MS) after trimethylsilylation. The method was validated using bile samples from immature female rainbow trout, which had been exposed to either tap water or an undiluted estrogenic effluent for 10 days. Hydrolysis of bile from effluent-exposed fish was complete within 16 h add most of the estrogenic activity in the bile was released by 3-glucuronidase rather than sulfatase or 3-glucosidase treatment. The estrogenic activity of hydrolysed bile from effluent-exposed fish ranged between 530 and 1440 ng E2eq/mL and was 17-48-fold greater than the activity of bile from reference fish exposed to tap water. The estrogenic activity of bile samples decreased with time in storage (at-70 degrees C by 7% per month). The recovery of estrogenic activity from SPE was 96 +/- 7% (mean +/- SD), from HPLC fractionation 87 +/- 7% and for the whole method 81 +/- 7% (n = 7). 17beta-Estradiol, estrone, 17alpha-ethinylestradiol, nonylphenol and short-chain nonylphenol polyethoxylates were all identified from GC-MS analysis of active HPLC fractions of bile from effluent-exposed trout, whereas only 17beta-estradiol was detected in bile from fish exposed to tap water. There were also several other minor estrogenic components, at present unidentified, in bile of effluent-exposed fish. The work shows that fractionation of fish bile is a useful approach to identifying mixtures of estrogenic contaminants taken up by fish from WwTW effluents and has the potential for application in the detection of other endocrine disrupting chemicals in fish tissues.
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PMID:Analytical methodology for the identification of estrogenic contaminants in fish bile. 1579 52


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