Overexpression of 17 beta-Hydroxysteroid Dehydrogenase Type 1 Increases the Exposure of Endometrial Cancer to 17 beta-Estradiol

Karlijn M. C. Cornel, Roy F. P. M. Kruitwagen, Bert Delvoux, Laura Visconti, Koen K. Van de Vijver, Joanna M. Day, Toon Van Gorp, Rob J. J. Hermans, Gerard A. Dunselman, Andrea Romano*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Context: The local interconversions between estrone (low activity) and 17 beta-estradiol (potent compound) by 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) can lead to high 17 beta-estradiol generation in endometrial cancer (EC). Objective: Examine the balance between the 17 beta-HSDs reducing estrone to 17 beta-estradiol (types 1, 5, 12, and 7) and those oxidizing 17 beta-estradiol to estrone (2, 4, and 8), in EC. Patients and Methods: Reducing and oxidizing 17 beta-HSD activities (HPLC) and mRNA level (RT-PCR) were assessed in normal post-menopausal (n = 16), peritumoral endometrium (normal tissue beside cancer, n = 13), and 58 EC (29 grade 1, 18 grade 2, 11 grade 3). Results: Grade 1 EC displayed a shifted estrone reduction/17 beta-estradiol oxidation balance in favor of 17 beta-estradiol compared with controls. This was more pronounced among estrogen receptor-alpha (ER-alpha)-positive biopsies. Type 1 17 beta-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-alpha-positive grade 1 EC than controls. The mRNA coding for types 4, 5, 7, 8, and 12 17 beta-HSD did not vary, whereas that coding for type 2 17 beta-HSD was increased in high-grade lesions compared with controls. Three-dimensional ex vivo EC explant cultures demonstrated that 17 beta-HSD type 1 generated 17 beta-estradiol from estrone and increased tumor cell proliferation. Additional in vitro studies using EC cells confirmed that in the presence of 17 beta-HSD type 1, estrone induced estrogen signaling activation similarly to 17 beta-estradiol. Therefore, estrone was reduced to 17 beta-estradiol. Conclusions: Type 1 17 beta-HSD increases 17 beta-estradiol exposure in grade 1 EC, thus supporting tumor growth. This enzyme represents a potential therapeutic target. (J Clin Endocrinol Metab 97: E591-E601, 2012)
Original languageEnglish
Pages (from-to)E591-E601
JournalJournal of Clinical Endocrinology & Metabolism
Volume97
Issue number4
DOIs
Publication statusPublished - Apr 2012

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