Steroid Sulfatase Research Articles

Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

Acquired Cryptorchidism in a 12-Year-old with X-Linked Ichthyosis (XLI)

Cryptorchidism is a broad term encompassing several distinct entities. True, false cryptorchidism and ectopia testis are congenital disorders. Rarely, cryptorchidism has acquired character. Testicular ascent is also sometimes known as acquired cryptorchidism with an unclear association. Various extracutaneous abnormalities have been reported in some patients with an increased incidence of testicular cryptorchidism. X-linked ichthyosis is a genetic disorder of keratinization characterized by a generalized desquamation of large, adherent, dark brown scales. Steroid sulfatase (STS) deficiency is one of the causes of ichthyoses. STS genes on the X chromosome is responsible for this disease. Herein we report a case of STS deficiency complicated with an acquired cryptorchidism. A 12-yearold- boy with STS deficiency was referred to our hospital because of emptiness of his right scrotum. In early childhood at 5 years of age his skin was excessively dry and scaly by visible scaling and/or hyperkeratosis of most or all the skin in the lower extremity. The child underwent immediate orchiopexy via a groin approach and the testis was successfully mobilized into the scrotum.

Genetic Study of X-Linked Recessive Ichthyosis in Eastern Ukraine

X-linked recessive ichthyosis (OMIM 308100) is a form of ichthyosis caused by abnormal keratinization and can result in disability, social maladaptation, and decreased quality of life for patients and their families. In most cases the disease is caused by a complete or partial deletion of the steroid sulfatase (STS) gene. This study estimated the prevalence of X-linked recessive ichthyosis, the inbreeding coefficient (or fixation index) FST, and the selection coefficient in individuals of eastern Ukraine (namely, Kharkiv oblast). The genealogical method was used to assess the genetic structure of families with a history of this disease. Fluorescent in situ hybridization (FISH) was carried out to detect the deletion of the STS gene in patients and their relatives. The prevalence of the disease in eastern Ukraine was 1.5 × 10–4 males, it ranged from 4.9 × 10–5 to 4.9 × 10–4 males in the districts, and from 2.2 × 10–4 males in the town of Krasnograd to 3.7 × 10–3 males in a village of Balakliia district. The burden of X-linked recessive ichthyosis was found to be positively correlated with the inbreeding coefficient FST in all the studied districts (r = 0.976). Over the past 10 years, the inbreeding coefficient FST increased 1.8 times and the prevalence of X-linked recessive ichthyosis increased 1.4–4.3 times in most districts of the region. The clinical genealogical analysis of nine large families revealed no females with X-linked recessive ichthyosis among relatives of probands, while 21.4% (n = 14) of the first-degree male relatives and 12.0% (n = 25) of the second-degree male relatives had ichthyosis. In most patients and their mothers from eastern Ukraine, FISH detected an interstitial deletion of the STS gene, ish del(X)(p22.31p22.31)(STS-), but no KAL1 gene deletions. In men with X-linked recessive ichthyosis, the average number of children per person was 2.5 times lower than in healthy relatives, and their offspring was characterized by the prevalence of females over males in a 3 : 1 ratio. In obligate heterozygous females, the average number of children per person was 2.2, and the sex ratio in the offspring approached 1 : 1.

MiRNA-mediated alteration of sulfatase modifying factor 1 expression using self-assembled branched DNA nanostructures.

Sulfatase enzymes catalyze sulfate ester hydrolysis, thus deficiencies of sulfatases lead to the accumulation of biomolecules resulting in several disorders. One of the important sulfatases is estrone sulfatase that converts inactive estrone sulfate to active estradiol. Posttranslational modification of highly conserved cysteine residue leads to unique formylglycine in the active site of sulfatases being critical for its catalytic activity. The essential factor responsible for this modification of sulfatase is Sulfatase-Modifying Factor 1 (SUMF1). The role of estrone sulfatase is well evident in breast cancer progression. However, the function and regulation of SUMF1 in cancer are not studied. In the present study, for the first time, we have assessed the expression of SUMF1 in breast cancer and report the oncogenic behavior upon overexpression of SUMF1. Although increased expression or activity of SUMF1 is anticipated based on its function, the expression of SUMF1 was found to be reduced in breast cancer cells at both mRNA and protein levels. An estrogen receptor (ER) dependent expression of SUMF1 was observed and higher SUMF1 expression is associated with improved breast cancer patient survival in ER-positive cases. However, high SUMF1 expression leads to reduced median survival in ER-negative breast cancer patients. Putative binding sites for miRNAs-106b-5p, 128-3p and 148b-3p were found at 3′-UTR of SUMF1. Since self-assembled branched DNA (bDNA) structures have emerged as a highly efficient strategy for targeting multiple miRNAs simultaneously, we studied the alteration in SUMF1 expression using bDNA nanostructures with a complementary sequence to miRNAs. The findings suggest the involvement of co-regulators and repressors in miRNA-mediated SUMF1 expression in breast cancer cells and reveal the therapeutic potential of SUMF1 in endocrine-related malignancies.

Design, synthesis and biological evaluation of combretastatin A-4 sulfamate derivatives as potential anti-cancer agents.

A series of combretastatin A-4 (CA-4) sulfamate derivatives were synthesized and their structure-activity relationship on tubulin, arylsulfatase and tumor cell antiproliferation inhibition was studied. Among them, compound 16a showed excellent potency as well as CA-4 under the same conditions against six tumor cells including HTC-116, HeLa, HepG2, MGC803, MKN45 and MCF-7 cells, respectively. Molecular docking revealed that several important hydrogen bond interactions were formed between the sulfamate group of 16a and the colchicine binding site of tubulin and steroid sulfatase respectively. Although compound 16a was less active than CA-4 in regard to its in vitro activity as an inhibitor of tubulin polymerization, it was effective as an inhibitor of arylsulfatase. This novel combretastatin A-4 sulfamate derivative has the potential to be developed as a dual inhibitor of tubulin polymerization and arylsulfatase for cancer therapy.

Suppressed estrogen supply via extra-ovarian progesterone receptor membrane component 1 in menopause.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a Pgrmc1 heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve Pgrmc1 hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, Pgrmc1 hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but PGRMC1 knockdown increased PR and STS expression. Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.

Гендерные локусы в ДНК-криминалистике и женском спорте

In forensic medicine, it is necessary to establish the sexual identity of the owner of the analyzed biological material. To do this, it is necessary to use PCR to detect specific DNA sequences that are characteristic only of the Y chromosome. For these purposes, a number of loci are used, located on both the Y and X chromosomes but carrying certain differences in the nucleotide sequences (alpha satellites DYZ and DXZ; amelogenin loci AMELY and AMELX; STS steroid sulfatase genes; the genes of the neuroligin NLG4Y and NLG4X, etc.), and those located only on the Y-chromosome (sex-determining region SRY; gene of the specific testicular protein TSPY, etc.). At the same time, forensic experts often deal with damaged or old samples in which the DNA has been destroyed and extended fragments in it may simply not be, as a result of which false negative results will be formed. Thus, in DNA forensics, when detecting gender loci, the sizes of amplicons should tend to the minimum possible. Therefore, in this review article, a certain emphasis was placed on the size of amplicons, and as practice shows, for most loci, their minimization is in demand. Moreover, such a PCR analysis in a number of cases (in XX-men, XY-women, in persons with other sex chromosome abnormalities, in people who deliberately changed their gender identity) it can lead to a false definition of the phenotypic sex due to the genetic characteristics of such individuals. As a result, the ongoing investigation of a crime, focused on the search for a representative of a particular gender, can go down the wrong path. A cardinal solution to this problem in DNA criminology can be a universal DNA registration of the entire population, which will allow for the biological traces with high accuracy to establish a specific person to whom these traces belong and his real sex will no longer be important and it will not be relevant to determine it with the help of PCR. In addition to forensic medicine, the problem of establishing gender also exists in women's sports. For a whole decade, the PCR method and some of the loci listed above were used for this purpose, but since 2011 PCR has been abandoned and instead the level of the male hormone testosterone has became determined. However, with the gender of female athletes, there are much more ethical issues than genetic ones.

Testicular steroid sulfatase overexpression is associated with Leydig cell dysfunction in primary spermatogenic failure.

Decreased testosterone (T) to LH ratio and increased 17β-estradiol (E2) serum concentrations represent a common finding among patients with severe spermatogenic failure, suggesting a concurrent Leydig cell steroidogenic dysfunction. Aromatase overexpression has been associated with increased serum and intratesticular E2 in these patients. However, it is unknown whether the sulfatase pathway contributes to the increased availability of active estrogens in patients with primary spermatogenic failure. To assess estrogen sulfotransferase (SULT1E1) and steroid sulfatase (STS) mRNA abundance in testicular tissue of patients with Sertoli cell-only syndrome (SCOS) and normal tissues, its association with serum and intratesticular hormone levels, and to explore the mRNA and protein testicular localization of both enzymes. Testicular tissues of 23 subjects with SCOS (cases) and 22 patients with obstructive azoospermia and normal spermatogenesis (controls) were obtained after biopsy. SULT1E1 and STS transcripts accumulation was quantified by RT-qPCR. For mRNA and protein localization, we performed RT-qPCR in Leydig cell clusters and seminiferous tubules isolated by laser-capture microdissection and immunofluorescence in testicular tissues. Serum and intratesticular hormones were measured by immunoradiometric assays. SULT1E1 mRNA accumulation was similar in both groups. The amount of STS mRNA was higher in cases (p=0.007) and inversely correlated with T/LH ratio (r=-0.402; p=0.02). Also, a near significant correlation was observed with intratesticular E2 (r=0.329, p=0.057), in agreement with higher intratesticular E2 in cases (p<0.001). Strong STS immunoreaction was localized in the wall of small blood vessels but not in Leydig cells. Both SULT1E1 and STS mRNA abundance was similar in Leydig cell clusters and the tubular compartment, except for lower SUTL1E1 mRNA in the seminiferous tubules of SCOS patients (p=0.001). Our results suggest that an unbalance of the STS/SULT1E1 pathway contributes to the testicular hyperestrogenic microenvironment in patients with primary spermatogenic failure and Leydig cell dysfunction.

New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives

In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line experiments have been carried out. We found that the lowest STS activities were measured in the presence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentrations, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and 16.83% in the same concentration range. Moreover, a determined IC50 value of 15.97 nM for 3L showed that this compound is a very promising candidate for further preclinical investigations.

Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.

Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer. STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo. STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo. These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy.

Clinical features and genetic analysis of two Chinese families with X-linked ichthyosis.

ObjectiveRecessive X-linked ichthyosis (RXLI) caused by deficiency of the steroid sulfatase gene (STS) has a reported prevalence of 1/2000 to 1/6000. The present study aimed to characterize the phenotypes and genotypes of two Chinese families with RXLI.MethodsThe patients were referred to the Family Planning Research Institute of Hunan Province for genetic counseling. Their skin phenotypes were photographed, and venous blood was drawn and used for chromosomal microarray analysis (CMA).ResultsThe skin phenotype of the proband from the first family was characterized by generalized skin dryness and scaling, with noticeable dark brown, polygonal scales on his trunk and extensor surfaces of his extremities. The proband from the second family had an atypical phenotype showing mild skin dryness over his entire body, slight scaling on his abdomen, and small skin fissures on his arms and legs. No mental disability or developmental anomaly was noted in either proband. CMA revealed that both probands carried a 1.4-Mb deletion on chromosome Xp22.31 involving four Online Mendelian Inheritance in Man-listed genes including STS.ConclusionsOur findings add knowledge to the genotype and phenotype spectrum of RXLI, which may be helpful in genetic counseling and prenatal diagnosis.

Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank.

Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and higher rates of developmental and mood disorders/traits, possibly related to the smaller volume of some basal ganglia structures. The consequences of duplication of the same genomic region have not been systematically assessed in large or adult samples, although evidence from case reports/series has indicated high rates of developmental phenotypes. We compared multiple measures of physical and mental health, cognition and neuroanatomy in male (n = 414) and female (n = 938) carriers of 0.8–2.5 Mb duplications spanning STS, and non-carrier male (n = 192, 826) and female (n = 227, 235) controls from the UK Biobank (recruited aged 40–69 from the UK general population). Clinical and self-reported diagnoses indicated a higher prevalence of inguinal hernia and mania/bipolar disorder respectively in male duplication carriers, and a higher prevalence of gastro-oesophageal reflux disease and blistering/desquamating skin disorder respectively in female duplication carriers; duplication carriers also exhibited reductions in several depression-related measures, and greater happiness. Cognitive function and academic achievement did not differ between comparison groups. Neuroanatomical analysis suggested greater lateral ventricle and putamen volume in duplication carriers. In conclusion, Xp22.31 duplications appear largely benign, but could slightly increase the likelihood of specific phenotypes (although results were only nominally-significant). In contrast to deletions, duplications might protect against depressive symptoms, possibly via higher STS expression/activity (resulting in elevated endogenous free steroid levels), and through contributing towards an enlarged putamen volume. These results should enable better genetic counselling of individuals with Xp22.31 microduplications.

Update on adrenarche.

Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair. The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta. The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.

PT090 - Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide

PT090 - Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide

Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis

The potential inhibitory effect of diverse triazolyl-ferrocene steroids on key enzymes of the estrogen biosynthesis was investigated. Test compounds were synthesized via copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes using our efficient methodology published previously. Inhibition of human aromatase, steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activities was investigated with in vitro radiosubstrate incubations. Some of the test compounds were found to be potent inhibitors of the STS. A compound bearing ferrocenyl side chain on the C-2 displayed a reversible inhibition, whereas C-16 and C-17 derivatives displayed competitive irreversible binding mechanism toward the enzyme. 17α-Triazolyl-ferrocene derivatives of 17β-estradiol exerted outstanding inhibitory effect and experiments demonstrated a key role of the ferrocenyl moiety in the enhanced binding affinity. Submicromolar IC50 and Ki parameters enroll these compounds to the group of the most effective STS inhibitors published so far. STS inhibitory potential of the steroidal ferrocenes may lead to the development of novel compounds able to suppress in situ biosynthesis of 17β-estradiol in target tissues.

Estrogen Formation and Inactivation Following TBI: What we Know and Where we Could go.

Traumatic brain injury (TBI) is responsible for various neuronal and cognitive deficits as well as psychosocial dysfunction. Characterized by damage inducing neuroinflammation, this response can cause an acute secondary injury that leads to widespread neurodegeneration and loss of neurological function. Estrogens decrease injury induced neuroinflammation and increase cell survival and neuroprotection and thus are a potential target for use following TBI. While much is known about the role of estrogens as a neuroprotective agent following TBI, less is known regarding their formation and inactivation following damage to the brain. Specifically, very little is known surrounding the majority of enzymes responsible for the production of estrogens. These estrogen metabolizing enzymes (EME) include aromatase, steroid sulfatase (STS), estrogen sulfotransferase (EST/SULT1E1), and some forms of 17β-hydroxysteroid dehydrogenase (HSD17B) and are involved in both the initial conversion and interconversion of estrogens from precursors. This article will review and offer new prospective and ideas on the expression of EMEs following TBI.

Recent Studies on Aromatase and Sulfatase Involved in Breast Cancer and their Inhibitors

Enzyme aromatase uses several androgen substrates for the biosynthesis of estrogen, i.e. conversion of androstenedione to estrone and testosterone to biologically potent estradiol. Aromatase inhibitors (AIs) such as anastrozole, letrozole and exemestane have been established in standard endocrine therapy of breast cancer, by interfering with estrogen signaling cascade. Steroid sulphatase (STS) regulates the level of active oestrogens and androgens in human target organs and steroidogenic tissues, which have a key role in hormone dependent breast cancers (HDBC). Sulfatase is still under the exploration stage and is yet to emerge as a potential therapeutic target in breast cancer. The discovery of estrone 3-O-sulfamate (EMATE), a highly potent irreversible STS inhibitor, accelerated the development of potent steroidal and nonsteroidal STS inhibitors. Attempts are also being made for the development of dual inhibitors of AI and STS, as an alternative approach to overcome the acquired resistance. This review includes the molecular structures and biochemistry of aromatase and sulphatase enzymes. The advances in the development of inhibitors of the two enzymes have also been outlined.

PD59-09 TARGETING STEROID SULFATASE WITH NOVEL INHIBITORS SUPPRESSES CRPC TUMOR GROWTH AND IMPROVES RESPONSE TO ENZALUTAMIDE

INTRODUCTION AND OBJECTIVE:Steroid sulfatase (STS) is a key enzyme that catalyzes the hydrolysis of DHEAS to the biologically active DHEA, which is further metabolized to active androgens that bind...

Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

BackgroundX-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been...

A new series of aryl sulfamate derivatives: Design, synthesis, and biological evaluation

Steroid sulfatase (STS) has recently emerged as a drug target for management of hormone-dependent malignancies. In the present study, a new series of twenty-one aryl amido-linked sulfamate derivatives 1a-u was designed and synthesized, based upon a cyclohexyl lead compound. All members were evaluated as STS inhibitors in a cell-free assay. Adamantyl derivatives 1h and 1p-r were the most active with more than 90% inhibition at 10 µM concentration and, for those with the greatest inhibitory activity, IC50 values were determined. These compounds exhibited STS inhibition within the range of ca 25–110 nM. Amongst them, compound 1q possessing a o-chlorobenzene sulfamate moiety exhibited the most potent STS inhibitory activity with an IC50 of 26 nM. Furthermore, to assure capability to pass through the cell lipid bilayer, compounds with low IC50 values were tested against STS activity in JEG-3 whole-cell assays. Consequently, 1h and 1q demonstrated IC50 values of ca 14 and 150 nM, respectively. Thus, compound 1h is 31 times more potent than the corresponding cyclohexyl lead (IC50 value = 421 nM in a JEG-3 whole-cell assay). Furthermore, the most potent STS inhibitors (1h and 1p-r) were evaluated for their antiproliferative activity against the estrogen-dependent breast cancer cell line T-47D. They showed promising activity with single digit micromolar IC50 values (ca 1–6 µM) and their potency against T-47D cells was comparable to that against STS enzyme. In conclusion, this new class of adamantyl-containing aryl sulfamate inhibitor has potential for further development against hormone-dependent tumours.