Steroid Sulfatase and Estrogen Sulfotransferase in Human Endometrial Carcinoma

Utsunomiya, Hiroki; Itō, Kiyoshi; Suzuki, Takashi; Kitamura, Taro; Kaneko, Chika; Nakata, Taisuke; Niikura, Hitoshi; Okamura, Koji; Yaegashi, Nobuo; Sasano, Hironobu

doi:10.1158/1078-0432.ccr-04-0040

Cited by 81 publications

(70 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In human endometrium and in endometrial disorders, steroidogenesis is believed to occur in both epithelial and stromal cells. (37)(38)(39)(40) There was a significant inverse correlation between DAX-1 immunoreactivity and histological grade in endometrial carcinoma. In addition, DAX-1 immunoreactivity in normal endometrium during the secretory phase and in endometrial hyperplasia was significantly higher than that in endometrial carcinoma.…”

Section: Discussionmentioning

confidence: 94%

“…These results all suggest that DAX-1 is likely to play a very important role in the maintenance of hormonal environments to prepare for implantation by acting as corepressor for ER, resulting in diminished local estrogenic actions together with 17β-hydroxysteroid dehydrogenase (17β HSD) type 2, which catalyzes the oxidation of 17β-estradiol (E2) to estrone (E1) in endometrial mucosa of the secretory phase. (40) Estrogens are also considered to play very important roles in the development of endometrial hyperplasia. Some cases of endometrial hyperplasia, especially atypical hyperplasia, are considered to be precursors of endometrial endometrioid adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Saito¹,

Itō²,

Suzuki³

et al. 2005

Cancer Science

Self Cite

View full text Add to dashboard Cite

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERα α α α (P = 0.006) and ERβ β β β LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis. (Cancer Sci 2005; 96: 645-652) E ndometrial carcinoma is one of the most common pelvic malignancies among women worldwide, and its incidence has recently increased.(1,2) In situ estrogen metabolism, including synthesis and degradation, has been recently recognized as a very important factor in the development and progression of various human estrogen-dependent neoplasms, including endometrial carcinoma, especially the endometrioid type. (3,4) In endometrial carcinoma, in situ 17β-estradiol (E2) availability has been reported to be closely associated with the pathogenesis and development of endometrial proliferative disorders including endometrial hyperplasia and carcinoma, especially the endometrioid type.(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family.(6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, vent...

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Saito¹,

Itō²,

Suzuki³

et al. 2005

Cancer Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both STS and EST immunoreactivity have been detected in 86% and 29% of endometrial carcinomas cases, respectively. In addition, the STS/EST ratio was associated significantly with poor prognosis in endometrial carcinoma patients [25]. Therefore, increased STS and decreased EST expression in both human breast and endometrial carcinomas may result in the increased availability of biologically active estrogens in situ.…”

Section: ) Steroid Sulfatase (Sts) and Estrogen Sulfotransferase (Est)mentioning

confidence: 99%

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

et al. 2007

Self Cite

View full text Add to dashboard Cite

Abstract. Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered "estrogen-dependent malignancies". In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) γ ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma.

show abstract

“…The other major source of estrogens is estrone sulfate, an inactive conjugated form abundant in the circulation. Estrone sulfate is desulfated to estrone by steroid sulfatase (STS) and estrone is inactivated by estrogen sulfotransferase (EST) (Utsunomiya et al 2004, Colette et al 2013. Understanding how the aberrant expression of these enzymes in endometriosis contributes to local estrogen production and metabolism will allow the development of improved therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Dienogest reduces HSD17β1 expression and activity in endometriosis

Mori¹,

Ito²,

Miyata³

et al. 2015

Journal of Endocrinology

View full text Add to dashboard Cite

Endometriosis is an estrogen-dependent disease. Abnormally biosynthesized estrogens in endometriotic tissues induce the growth of the lesion and worsen endometriosis-associated pelvic pain. Dienogest (DNG), a selective progesterone receptor agonist, is widely used to treat endometriosis and efficiently relieves the symptoms. However, its pharmacological action remains unknown. In this study, we elucidated the effect of DNG on enzymes involved in local estrogen metabolism in endometriosis. Surgically obtained specimens of 23 ovarian endometriomas (OE) and their homologous endometrium (EE), ten OE treated with DNG (OE w/D), and 19 normal endometria without endometriosis (NE) were analyzed. Spheroid cultures of stromal cells (SCs) were treated with DNG and progesterone. The expression of aromatase, 17b-hydroxysteroid dehydrogenase 1 (HSD17b1), HSD17b2, HSD17b7, HSD17b12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17b1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression of aromatase, HSD17b1, STS, and EST, along with decreased HSD17b2 expression, when compared with stromal cells from normal endometria without endometriosis (NESCs) (P!0.01) or stromal cells from homologous endometrium (EESCs) (P!0.01). In OESCs, DNG inhibited HSD17b1 expression and enzyme activity at 10 K7 M (P!0.01). Results of immunohistochemical analysis displayed reduced HSD17b1 staining intensity in OE w/D (P!0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17b1, contributing to a therapeutic effect of DNG on endometriosis.

show abstract

Steroid Sulfatase and Estrogen Sulfotransferase in Human Endometrial Carcinoma

Cited by 81 publications

References 43 publications

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

Dienogest reduces HSD17β1 expression and activity in endometriosis

Contact Info

Product

Resources

About