Steroid sulphatase inhibitors: A new endocrine therapy

Reed, M. J.; Purohit, A; Howarth, Nicola M.; Bvl., Potter

doi:10.1358/dof.1984.009.07.595793

Cited by 13 publications

(21 citation statements)

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“…The function of 17-HSD type IV is similar in that it oxidizes oestrogens and androgens (Adamski et al, 1992). Much of the E1 formed from androstendione is converted by STS to oestrone sulphate, which acts as a reservoir for the formation of E1 via STS (Reed et al, 1994). One could speculate that to produce the biologically more potent E2 associated with breast tumours, the aromatase and STS complexes then take over by converting testosterone or oestrone sulphates into E2.…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

et al. 1999

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Summary Enzymes modulating local steroid availability play an important role in the progression of human breast cancer. These include isoforms of 17β-hydroxysteroid dehydrogenase (17-HSD), aromatase and steroid sulphatase (STS). The aim of this study was to investigate the expression, by reverse transcription polymerase chain reaction, of 17-HSD types I-IV, aromatase and steroid STS in a series of 51 human breast tumour biopsies and 22 primary cultures of epithelial and stromal cells derived from these tumours, giving a profile of the steroidregulating network for individual tumours. Correlations between enzyme expression profiles and expression of the interleukin (IL)-6 gene were also sought. All except one tumour expressed at least one isoform of 17-HSD, either alone or in combination with aromatase and STS. Expression of 17-HSD isoforms I-IV were observed in nine tumours. Of the 15 tumours which expressed three isoforms, a combination of 17-HSD II, III and IV was most common (6/15 samples). The majority of tumours (n = 17) expressed two isoforms of 17-HSD with combinations of 17-HSD II and IV predominant (7/17 samples). Eight tumours expressed a single isoform and of these, 17-HSD I was in the majority (5/8 samples). In primary epithelial cultures, enzyme expression was ranked: HSD I (86%) > STS (77%) > HSD II (59%) > HSD IV (50%) = aromatase (50%) > HSD III (32%). Incidence of enzyme expression was generally reduced in stromal cultures which were ranked: HSD I (68%) > STS (67%) > aromatase (48%) > HSD II (43%) > HSD IV (28%) > HSD III (19%). Expression of IL-6 was associated with tumours that expressed ≥ 3 steroid-converting enzymes. These tumours were of higher grade and tended to come from patients with family history of breast cancer. In conclusion, we propose that these enzymes work in tandem with cytokines thereby providing sufficient quantities of bioactive oestrogen from less active precursors which stimulates tumour growth.

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Section: Discussionmentioning

confidence: 99%

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

et al. 1999

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“…In addition, it has been observed that in postmenopausal patients with breast cancer, oestrogens levels in specimens were found to be several folds higher than those of plasma [32,33]. Although oestrogens levels decline sharply after the menopause, it has been reported that in some breast tumours, in situ formation of oestrogens can make an important contribution to the oestrogen content of breast cancer cells [34,35]. Moreover, experimental evidence using xenograft models provides direct proof that locally produced oestrogen can stimulate the growth of oestrogendependent MCF-7 human breast tumours to a greater extent than can oestrogen delivered via an endocrine mechanism [17].…”

Section: Oestrogen Productionmentioning

confidence: 99%

Oestrogen producing enzymes and mammary carcinogenesis: a review

Subramanian

Salhab

Mokbel

2007

Breast Cancer Res Treat

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There is a large and compelling body of epidemiological and experimental evidence that oestrogens are instrumental in the aetiology of breast cancer. Their mechanisms of action are varied, including stimulation of cellular proliferation through receptor-mediated hormonal activity, increasing genetic mutation rates through cytochrome P450-mediated metabolic activation, and induction of aneuploidy. The local biosynthesis of oestrogens especially in postmenopausal women is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma and the over-expression of regulatory enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this article we highlight the role of CYP19 gene expression and aromatase activity in mammary carcinogenesis. Other oestrogen producing (17-beta-hydroxysteroid dehydrogenase and steroid sulphatase) and catalyzing enzymes (3-beta-hydroxysteroid dehydrogenase, Oestrogen sulfotransferase, CYP1A1, CYP1B1, and CYP3A4) are also discussed in some detail. Understanding the mechanisms that regulate these enzymes is crucial to the development of new endocrine therapies in post-menopausal females with hormone dependant breast cancer. Currently, third generation aromatase inhibitors has revolutionized the treatment of oestrogen dependant breast cancer. However, the important role of both STS and 17-beta-HSD type 1 in local oestrogen production provides novel potential targets for endocrine therapy. Such endocrine therapy is currently being explored and the development of STS inhibitors, combined aromatase/steroid sulfatase inhibitors and 17-beta-HSD type 1 inhibitors is underway with promising initial results.

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“…Estrone sulfate (E1S) appears to be a major source of active estrogens in mammary tumors, especially in women after menopause (for detailed reviews see [52][53][54][55][56] ). While E1S itself does not bind to estrogen receptors, 57 it is converted in the tissue first by STS to unconjugated E1 and then by a reducing enzyme (17b-hydroxysteroid dehydrogenase) to E2, which binds to the receptors with high affinity (Fig.…”

Section: B Hormone-dependent Cancermentioning

confidence: 99%

“…64,70 Also DHEAS-stimulated breast cancer cell growth can be blocked by STS inhibitors. 64 Similar to breast cancer, estrogen-dependent cancer of the uterine endometrium has been proposed as potential indication for STS inhibitors 54 ; in fact, STS appears to be overexpressed in endometrial carcinoma as compared to benign tissue. 71,72 The growth of prostatic tumors is stimulated by androgens; whereas it is clear that testicular androgens (testosterone and dihydrotestosterone) supplied from the circulation stimulate prostate cancer cells, active androgens produced in the tumor tissue from the abundant systemic precursor DHEAS may also play a role (reviewed in Ref.…”

Section: B Hormone-dependent Cancermentioning

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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Steroid sulphatase inhibitors: A new endocrine therapy

Cited by 13 publications

References 0 publications

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

Oestrogen producing enzymes and mammary carcinogenesis: a review

Steroid sulfatase inhibitors

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