Estrone sulfate-sulfatase and 17β-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence

Pasqualini, Jörge R.; Chétrite, G.; Nguyen, B.-L.; Maloche, C.; Delalonde, Laurence; Talbi, Mohamed; Feinstein, M.-C.; Blacker, C. P.; Botella, J.; Pâris, J.

doi:10.1016/0960-0760(95)00116-h

Cited by 75 publications

(25 citation statements)

References 26 publications

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“…Progestins have been shown to inhibit the reductive 17␤-HSD activity as well as to stimulate the oxidative 17␤-HSD activity, respectively in BC cell lines. In contrast, sulfotransferase activity was shown to be increased in MCF-7 and T-47D cell lines when progestins were added [32,41,60,61]. A recent study in BC cells demonstrated different effects on various enzymes depending on what type of progestin and estradiol was combined with [44].…”

Section: Discussionmentioning

confidence: 99%

“…Breast tissue and mammary cancer cells have been shown to possess the enzymatic systems necessary for the intratumoral biosynthesis of estrogens from precursor molecules circulating in plasma. Three main enzymes are important in this process: aromatase, which converts androgens to estrogens [18][19][20], E 1 S-sulfatase (STS) which hydrolizes E 1 S to E 1 [20][21][22][23][24][25][26][27][28], and 17␤-hydroxysteroid dehydrogenase type 1 (17␤HSD-1) which reduces E 1 to E 2 [29][30][31][32]. The activity of STS in breast tumors has been shown to be 10-500-fold higher than aromatase activity [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

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Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Stute¹,

Nisslein

Götte³

et al. 2007

Maturitas

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Objectives: To investigate the effect of black cohosh on the estrogen biosynthesis in the breast in vitro. Methods: Steroid sulfatase (STS) activity was studied in normal breast tissue obtained from pre-and postmenopausal women undergoing reduction mammoplasty. STS protein expression was studied by immunohistochemistry and western blotting. Breast tissue was incubated in vitro without or with black cohosh (iCR) at concentrations ranging from 0.1 mg/ml to 1 ng/ml. STS activity was evaluated by incubating homogenized breast tissue with [ 3 H]-estrone sulfate, separating the formed products, estrone (E 1 ) and estradiol (E 2 ), by thin layer chromatography and measuring the amounts of E 1 and E 2 by scintillation counting. Results: STS protein expression and enzymatic activity were detected in all specimens investigated. In all groups, significantly more E 1 than E 2 was produced. Local estrogen formation was decreased in premenopausal breast tissue by treatment with iCR at 0.1 mg/ml (p ≤ 0.05). Conclusions: iCR decreases local estrogen formation in normal human breast tissue in vitro. This may contribute to the lack of hormonal effects of black cohosh in breast tissue observed in previous studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Stute¹,

Nisslein

Götte³

et al. 2007

Maturitas

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“…8) as potential STS inhibitors, most of them marketed drugs for estrogen-related disorders or as oral contraceptives (reviewed in Refs. 132,133). In many of these studies, intact breast tumor cells were incubated with labeled E1S and the formation of E1 and E2 was measured in the presence of progestins; this experimental setting leaves it open whether a compound acts as direct STS inhibitor (by binding to the target protein), or whether compounds influence cellular levels of active STS (e.g., by acting on STS transcription or post-translational modification).…”

Section: Progestinsmentioning

confidence: 99%

Steroid sulfatase inhibitors

Nußbaumer

Billich

2004

Medicinal Research Reviews

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Steroid sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3-hydroxy steroids, which are inactive transport or precursor forms of the active 3-hydroxy steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential new therapeutic agents for the treatment of estrogen- and androgen-dependent disorders. Indications range from cancers of the breast, endometrium and prostate to androgenetic alopecia and acne. In this review, we give a comprehensive summary of the current knowledge and problems in the field of medicinal chemistry of STS inhibitors. The various types of inhibitors are presented and their structure-activity relationships are discussed. In addition to potent arylsulfamate-based, irreversible inhibitors, novel types of reversible inhibitors were recently discovered. The recent publication of the X-ray structure of STS will further boost research activities on this attractive target.

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“…While the local production in bone and adipocytes might serve physiological needs, malignant breast tumors also appear to produce their own estradiol locally (Sasano et al 1997, Chetrite et al 2000, Belanger et al 2002. Intratumoral estrogen levels have been shown to be several folds higher than corresponding systemic levels (Pasqualini et al 1995). Although malignant breast tissue contains all the enzymes necessary for the local biosynthesis of estrogens, there is increasing evidence that the cytochrome P450 enzyme aromatase is mainly responsible for the elevated local levels of biologically active estradiol.…”

Section: Introductionmentioning

confidence: 99%

Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism

Singer

Fink-Retter²,

Gschwantler‐Kaulich³

et al. 2006

Endocr Relat Cancer

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The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (PZ0.00008, Fisher's exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (PZ0.00005, and P!0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (rZ0.35461, PZ 0.0009, Spearman's r test) and with the epithelial ER status (rZ0.29313, PZ0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.

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Estrone sulfate-sulfatase and 17β-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence

Cited by 75 publications

References 26 publications

Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Steroid sulfatase inhibitors

Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism

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