The sulfatase pathway as estrogen supply in endometrial cancer

Cornel, Karlijn M. C.; Delvoux, Bert; Saya, T.; Xanthoulea, Sofia; Konings, Gonda; Kruitwagen, Rfpm; Bongers, Marlies Y.; Kooreman, Loes; Romano, Andrea

doi:10.1016/j.steroids.2018.09.002

Cited by 12 publications

(8 citation statements)

References 32 publications

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“…In an IHC study, no STS expression was detected in normal endometrium tissue although it was detected in 86% of the cases of endometrial cancer tissue [ 42 ]. However, more recent studies on patient endometrial cancer tissue have not shown changes in STS mRNA or protein expression, compared to normal endometrial controls [ 43 , 44 ]. For ovarian cancer, Milewich and Porter originally found that STS was present in cells derived from ovarian cancers [ 45 ].…”

Section: Steroid Sulphatase Expression and Activitymentioning

confidence: 99%

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Foster

2021

Molecules

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Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter’s imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase–STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.

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Section: Steroid Sulphatase Expression and Activitymentioning

confidence: 99%

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Foster

2021

Molecules

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“…We and others have previously reported on the importance of the sulfatase pathway for E2 formation in EC tissue samples and model cell lines (Hevir-Kene and Rižner, 2015;Sinreih et al, 2017;Cornel et al, 2018). The crucial role of sulfatase was also confirmed in mouse endometrial cancer xenograft model where STS inhibitor STX64 significantly inhibited tumour growth (Foster et al, 2008).…”

Section: Discussionmentioning

confidence: 52%

In the Model Cell Lines of Moderately and Poorly Differentiated Endometrial Carcinoma, Estrogens Can Be Formed via the Sulfatase Pathway

Pavlič

Gjorgoska

Hafner

et al. 2021

Front. Mol. Biosci.

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Endometrial cancer (EC) is the most common gynecological malignancy in resource-abundant countries. The majority of EC cases are estrogen dependent but the mechanisms of estrogen biosynthesis and oxidative metabolism and estrogen action are not completely understood. Here, we evaluated formation of estrogens in models of moderately and poorly differentiated EC: RL95-2 and KLE cells, respectively. Results revealed high expression of estrone-sulfate (E1-S) transporters (SLCO1A2, SLCO1B3, SLCO1C1, SLCO3A1, SLC10A6, SLC22A9), and increased E1-S uptake in KLE vs RL95-2 cells. In RL95-2 cells, higher levels of sulfatase and better metabolism of E1-S to E1 were confirmed compared to KLE cells. In KLE cells, disturbed balance in expression of HSD17B genes led to enhanced activation of E1 to E2, compared to RL95-2 cells. Additionally, increased CYP1B1 expression and down-regulation of genes encoding phase II metabolic enzymes: COMT, NQO1, NQO2, and GSTP1 suggested decreased detoxification of carcinogenic metabolites in KLE cells. Results indicate that in model cell lines of moderately and poorly differentiated EC, estrogens can be formed via the sulfatase pathway.

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“…Moreover, CYP19A1 expression is also positively modulated by estrogen via ERα (Kinoshita & Chen 2003). Although a large amount of estrogens can be supplied locally via CYP19A1, the combined action of steroid sulfatase (STS) and the enzyme estrogen sulfotransferase (SULT1E1) also represents an important pathway for estrogen production (Cornel et al 2018). Clinically, patients with endometriosis present increased circulating estrogen levels, which has been associated with higher expression of ERα within endometriotic lesions, leading to disease progression (Delvoux et al 2009, Huhtinen et al 2012, Andersen et al 2018.…”

Section: Discussionmentioning

confidence: 99%

Clotrimazole reduces endometriosis and the estrogen concentration by downregulating aromatase

et al. 2020

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This study aimed to analyse the effects of clotrimazole (CTZ) on estrogen production pathway in endometriosis progression. Experimental endometriosis was induced by autologous transplantation in female Wistar rats, and then the rats were treated with clotrimazole (200 mg/kg) or vehicle, both orally and intraperitoneally, for 15 consecutive days. Serum estrogen levels and vaginal smear analyses were performed and ERα (estrogen receptor alpha) and CYP19 (cytochrome P450 aromatase) levels in the endometriotic lesions were analysed morphologically and immunohistochemically. The clotrimazole group presented a reduction in serum estrogen levels, which were not influenced by the estrous cycle of the animals. The expression of ERα and CYP19 in endometriotic lesions was also reduced in the clotrimazole group compared to the control group. Moreover, clotrimazole treatment decreased the size of the lesions, as confirmed by histological examination, which showed glandular atrophy for both routes of administration. These results suggest that clotrimazole interferes with the estrogen production pathway by downregulating CYP19 and, therefore, reducing serum estrogen levels. Thus, the drug decreases endometriotic lesion size and consequently disease progression.

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The sulfatase pathway as estrogen supply in endometrial cancer

Cited by 12 publications

References 32 publications

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

In the Model Cell Lines of Moderately and Poorly Differentiated Endometrial Carcinoma, Estrogens Can Be Formed via the Sulfatase Pathway

Clotrimazole reduces endometriosis and the estrogen concentration by downregulating aromatase

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