Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer

Sinreih, Maša; Hevir, Neli; Rižner, Tea Lanišnik

doi:10.1016/j.cbi.2012.11.012

Cited by 34 publications

(33 citation statements)

References 36 publications

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“…Rižner & Penning (2014) reviewed the possible roles of AKR1 enzymes in human steroid metabolism and alluded on the possibility of AKR1C gene expression in endometrial carcinoma. However, AKR1C1 and AKR1C2 mRNA expression in cancerous endometrium did not differ significantly to that in adjacent control normal tissue (Smuc & Rizner 2009, Sinreih et al 2013. Therefore, it is unlikely that AKR1C1 and AKR1C2 serve as negative regulators of in situ production of DHT in endometrial carcinoma.…”

Section: :7mentioning

confidence: 82%

“…In normal endometrium, 17β-HSD2 immunoreactivity was present at all the cases of secretory phase, but not at any endometrial mucosa of proliferative phase. 17β-HSD2 mRNA expression was consistently detected in endometrial carcinoma compared with adjacent normal endometrium at menopausal status in several studies (Lépine et al 2010, Cornel et al 2012, Sinreih et al 2013. Therefore, the enzyme of 17β-HSD2 should play an important role to modify the balance of estrogen production in not only breast but also endometrial carcinoma.…”

Section: Androgen Action From the Viewpoint Of Therapeutic Targetmentioning

confidence: 97%

“…However, one group reported weaker protein expression of 17β-HSD5 in hyperplastic and cancerous endometrium compared with normal proliferative endometrium (Zakharov et al 2010) and no significant difference of mRNA expression between cancerous and normal endometrial tissues was detected in other groups (Cornel et al 2012, Sinreih et al 2013). In our previous study, 17β-HSD5 immunoreactivity was detected in 18/36 (50%) and 71/103 (69%) cases of endometrial hyperplasia and endometrioid endometrial carcinoma, respectively.…”

Section: β-Hsd5mentioning

confidence: 99%

“…Endometrial carcinoma tissue homogenates were associated with mRNA expression in the great majority of the cases examined. However, mRNA expression of 5α-Red2 was significantly down-regulated and that of 5α-Red1 was unchanged in endometrial carcinoma versus adjacent control endometrium, including proliferative, secretory and menopausal status (Sinreih et al 2013). Recently, we measured the tissue concentration of androgen and performed immunohistochemical analyses of AR and 5α-Reds in 36 endometrioid endometrial carcinoma cases .…”

Section: α-Reductasementioning

confidence: 99%

See 3 more Smart Citations

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

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In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

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Section: :7mentioning

confidence: 82%

Section: Androgen Action From the Viewpoint Of Therapeutic Targetmentioning

confidence: 97%

Section: β-Hsd5mentioning

confidence: 99%

Section: α-Reductasementioning

confidence: 99%

See 2 more Smart Citations

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…In this situation, that the excess of estrogen stimulation is not sufficiently counterbalanced by progesterone results in promoted mitogenesis, atypical hyperplasia, and the transition to malignant adenocarcinoma (Wang et al, 2014). The presence of increased endometrial proliferation rates at follicular phase of menstrual cycle, during which progestin levels are low, whereas estradiol levels are at normal premenopausal concentrations and increased endometrial cancer risk among women using exogenous estrogens without progestins are two important signs that verify this relation (Kaaks et al, 2002) Progesterone reduces estrogenic activity in the endometrium by enhancing the local synthesis of 17β-hydroxysteroid dehydrogenase and estrogen sulfotransferase (Sinreih et al, 2013). These enzymes play significant role in the conversion of estradiol into the less potent estrogen estrone, and into estrogen sulfates that are rapidly excreted from cells and from the body.…”

Section: Pcos Hyperestrogenism and Progesterone Deficiencymentioning

confidence: 99%

Polycystic Ovary Syndrome and Risk of Endometrial Cancer: a Mini-Review

Tokmak¹,

Kokanali²,

Güzel³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Konings

Cornel

Xanthoulea

et al. 2018

The Journal of Pathology

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The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17β-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer

Cited by 34 publications

References 36 publications

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Polycystic Ovary Syndrome and Risk of Endometrial Cancer: a Mini-Review

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

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