Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives

Abstract

Sulfatase (STS) and sulfotransferases (SULT) have important role in the biosynthesis and action of steroid hormones. STS catalyzes the hydrolysis of estrone-sulfate (E1-S) and dehydroepiandrosterone-sulfate (DHEA-S), while sulfotransferases catalyze the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate as a sulfate donor. These enzymes control the concentration of active estrogens and androgens in peripheral tissues. Aberant expression of STS and SULT genes has been found in both, benign hormone-dependent diseases and hormone-dependent cancers. The aim of this review is to present the current knowledge on the role of STS and SULT in gynecological cancers, endometrial (EC) and ovarian cancer (OC). EC is the most common and OC the most lethal gynecological cancer. These cancers primarily affect postmenopausal women and therefore rely on the local production of steroid hormones from inactive precursors, either DHEA-S or E1-S. Following cellular uptake by organic anion transporting polypeptides (OATP) or organic anion transporters (OAT), STS and SULT regulate the formation of active estrogens and androgens, thus disturbed balance between STS and SULT can contribute to the onset and progression of cancer. The importance of these enzymes in peripheral estrogen biosynthesis has long been recognized, and this review provides new data on the important role of STS and SULT in the formation and action of androgens, their regulation and inhibition, and their potential as prognostic biomarkers.

Keywords: androgens; estrogens; intracrinology; sulfatase; sulfotransferase.

Figure 1. Biosynthesis of estrogens and androgens from inactive precursors DHEA-S and E1-S

The most potent estrogen, estradiol (E2), can be formed from E1-S by the action of STS and 17β-hydroxysteroid dehydrogenases (HSD17B) (sulfatase pathway) or from DHEA-S, DHEA or androstenedione by the action of STS, 3β-hydroxysteroid dehydrogenases-Δ^5-4 isomerases (HSD3B1 or HSD3B2), aromatase (CYP19A1) and HSD17B enzymes (aromatase pathway). The most potent androgen, 5α-dihydrotesterone (DHT), can be formed from DHEA-S by the actions of STS, HSD3B1 or HSD3B2, aldo-keto reductase 1C3 (AKR1C3) and 5α-reductases types 1 or 2 (SRD5A1 and SRD5A2).

Figure 2. STS and SULT interconvert E1-S and E1, DHEA-S and DHEA

Steroid sulfatase catalyzes the hydrolysis of DHEA-S (A) and E1-S (B), while sulfotransferases (SULT) catalyse the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate (PAPS) as a sulfate donor.

Figure 3. STS, SULT and AR in EC – analysis of TCGA data

Analysis of TCGA EC transcriptome data from patients stratified into molecular subtypes; POLE-altered (n=48), MSI-high (n=142), NSMP (n=141) and TP53-altered (n = 151). Boxplots illustrate the expression of STS (A), SULT1E1 (B), SULT2A1 (C) and SULT2B1 (D). Androgen pathway activity in endometrial tumors with low STS (n=428) and high STS (n=54) expression, estimated with the Progeny package in R Studio (E). Correlation between STS and AR expression in EC (n=482) (F). Gene expression is expressed as log2(FPKM-uq+1). Data are presented as boxplots showing the median, first and third quartiles and whiskers as min-max values and the raw data as individual points. Significance levels: *P<0.05, **P<0.01,****P<0.0001 by Kruskal−Wallis followed by Dunn’s post-hoc test with Bonferroni correction (A−D), Mann−Whitney U test (E), Spearman’s rank correlation coefficient ρ (F). FPKM, fragments per kilobase of transcript per million mapped fragments; MSI, microsatellite instability; NSMP, non-specific molecular profile; POLE, polymerase ε; uq, upper quartile.

Figure 4. STS, SULT and AR in HGSOC – analysis of TCGA data

Analysis of TCGA HGSOC transcriptome data from patient stratified into molecular subtypes; immunoreactive (n=80), differentiated (n=98), proliferative (n=99) and mesenchymal (n=87). Boxplots illustrate the expression of STS (A), SULT1E1 (B), SULT2A1 (C) and SULT2B1 (D). Androgen pathway activity in HGSOC with low-STS (n=128) and high-STS (n=236) expression, as estimated using Progeny package in R Studio (E). Correlation between STS and AR expression in HGSOC (n = 364) (F). Gene expression is expressed in log2(FPKM-uq+1). Data are represented as boxplots showing the median, first and third quartiles and whiskers as min-max values and the raw data as individual points. Significance levels: *p<0.05, ****p<0.0001 by Kruskal-Wallis followed by Dunn’s post-hoc test with Bonferroni correction (A−D), Mann−Whitney U test (E), Spearman’s rank correlation coefficient ρ (F). FPKM, fragments per kilobase of transcript per million fragments mapped; HGSOC, high-grade serous ovarian cancer; uq, upper quartile.

Figure 5. STS and SULT in EC and HGSOC

Scheme summarising the current state of knowledge on the expression of STS and SULT in EC and HGSOC. Data are shown for POLE-mutated and TP53-mutated EC, with good and poor prognosis, respectively, and for HGSOC and the particularly proliferative subtype with relatively poor prognosis.