Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications

Pasqualini, Jörge R.; Chétrite, G.

doi:10.1016/s0960-0760(99)00082-5

Cited by 65 publications

(33 citation statements)

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“…Therefore, since both Tib and raloxifene were readily sulfated by human tissues the regulation of the levels of these sulfates may be critical in regulating their physiological functions especially in target tissues (12,13). Although conjugation with a sulfonate group is generally an inactivation process, sulfation is a reversible process since many sulfate esters can be hydrolyzed by STS activity (31,32). Desulfation regenerates the active form of the compound and renders it capable of exerting a biological effect.…”

Section: Discussionmentioning

confidence: 99%

“…Desulfation regenerates the active form of the compound and renders it capable of exerting a biological effect. Both the SULTs and STS are widely distributed in human tissues (6,7,31) although several of the SULT isoforms demonstrate important tissue specific activity in steroid metabolism (8,13,22,33). The sulfation of Tib and its active metabolites in human endometrial cells by SULT1E1 is important for preventing the estrogenic activity of Tib in human endometrial tissues by selecting the generation of the progestagenic Δ4-isomer (13).…”

Section: Discussionmentioning

confidence: 99%

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Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

Falany

2007

The Journal of Steroid Biochemistry and Molecular Biology

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Sulfation is important in the metabolism and inactivation of steroidal compounds and hormone replacement therapeutic (HRT) agents in human tissues. Although generally inactive, many steroid sulfates are hydrolyzed to their active forms by sulfatase activity. Therefore, the specific sulfotransferase (SULT) isoforms and the levels of steroid sulfatase (STS) activity in tissues are important in regulating the activity of steroidal and HRT compounds. Tibolone (Tib) is metabolized to three active metabolites and all four compounds are readily sulfated. Tib and the Δ4-isomer are sulfated at the 17β-OH group by SULT2A1 and the 17-sulfates are resistant to hydrolysis by human placental STS. 3α-OH and 3β-OH Tib can form both 3-and 17-monosulfates as well as disulfates. Only the 3β-sulfates are susceptible to STS hydrolysis. Raloxifene monosulfation was catalyzed by at least seven SULT isoforms and SULT1E1 also synthesizes raloxifene disulfate. SULT1E1 forms both monosulfates in a ratio of approximately 8:1 with the more abundant monosulfate migrating on HPLC identical to the SULT2A1 synthesized monosulfate. The raloxifene monosulfate formed by both SULT isoforms is sensitive to STS hydrolysis whereas the low abundance monosulfate formed by SULT1E1 is resistant. The benzothiophene sulfates of raloxifene and arzoxifene were hydrolyzed by STS whereas the raloxifene 4′-phenolic sulfate was resistant. These results indicate that tissue specific expression of SULT isoforms and STS could be important in the inactivation and regeneration of the active forms of HRT agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

Falany

2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…In this study, seven subjects withdrew due to breast tenderness in the CEE -MPA group compared with only three in the tibolone group. The differing incidences of breast tenderness in the two groups may be attributable to the oestrogen content of the CEE -MPA preparation, and the tissuespecific actions of tibolone that act to decrease oestradiol levels and cellular proliferation in the breast 7,8 .…”

Section: Discussionmentioning

confidence: 99%

“…These effects may be explained by tibolone's inhibition of sulphatase, resulting in decreased local oestradiol levels, and the stimulation of apoptosis as well as the inhibition of proliferation 7,8 .…”

Section: Introductionmentioning

confidence: 99%

Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women

Huber¹

2002

BJOG: An International Journal of Obstetrics and Gynaecology

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Objective To compare the effects of tibolone and conjugated equine oestrogens continuously combined with medroxyprogesterone acetate on bleeding rates, quality of life (QoL) and tolerability. Design A double-blind, randomised comparative trial.Setting Thirty-seven centres in six European countries.Population Five hundred and one postmenopausal women, under 65 years of age with an intact uterus.Interventions For 12 months, women received daily treatment with tibolone 2.5 mg (n ¼ 250), or conjugated equine oestrogens 0.625 mg continuously combined with medroxyprogesterone acetate 5 mg (CEE-MPA, n ¼ 251). Main outcome measures The primary outcome was vaginal bleeding rate during cycles 4 -6. The secondary outcomes were vaginal bleeding rate during cycles 1 -3, 7-9 and 10 -13, cumulative bleeding rate, QoL, wellbeing, climacteric symptoms, urogenital complaints and tolerability. Results Treatment with tibolone led to a significantly lower bleeding rate during cycles 4 -6 compared with CEE -MPA (15.0% vs 26.9%; P ¼ 0.004); there was a similar difference during cycles 1-3. Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital complaints. By intent-to-treat analysis, tibolone significantly improved sexual drive, interest and/or performance, compared with CEE -MPA at 12 months ( P ¼ 0.017). Although both treatments were well tolerated, there was a significantly lower incidence of breast tenderness with tibolone than CEE -MPA (2.4% vs 17.1%; P < 0.001). Conclusion The vaginal bleeding rate during cycles 4-6 was significantly lower in women using tibolone.Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital symptoms. Breast tenderness was significantly less frequent with tibolone.

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“…This complex system, shown in a simplified version in figure one, means that enormous local control over the types and amounts of steroids produces and specific to one tissue is possible. Results of numerous studies have demonstrated increased tissue estrogen content in human breasts, compared with serum and/or normal nonneoplastic tissues of the same patients (van Landeghem et al 1985, Pasqualini & Chetrite 1999, Chetrite et al 2000. In these studies, the tissue concentrations of E 1 and E 2 were generally several times higher than those detected in the plasma or in the area of the normal breast tissues of the same postmenopausal patients, despite markedly low levels of circulating estrogens.…”

Section: Intracrinologymentioning

confidence: 96%

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

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In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

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Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications

Cited by 65 publications

References 50 publications

Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

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