Details

Autor(en) / Beteiligte

• Konings, Gonda FJ
• Cornel, Karlijn MC
• Xanthoulea, Sofia
• Delvoux, Bert
• Skowron, Margaretha A
• Kooreman, Loes
• Koskimies, Pasi
• Krakstad, Camilla
• Salvesen, Helga B
• van Kuijk, Kim
• Schrooders, Yannick JM
• Vooijs, Marc
• Groot, Arjan J
• Bongers, Marlies Y
• Kruitwagen, Roy FPM
• Romano, Andrea

Titel

Blocking 17[beta]-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

Ist Teil von

• The Journal of pathology, 2018-02, Vol.244 (2), p.203

Ort / Verlag

Bognor Regis: Wiley Subscription Services, Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• The enzyme type 1 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD-1), responsible for generating active 17[beta]-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 17[beta]-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 17[beta]-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17[beta]-HSD-1 activity could be blocked by a specific 17[beta]-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17[beta]-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 17[beta]-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17[beta]-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17[beta]-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 17[beta]-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, 17[beta]-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17[beta]-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17[beta]-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.