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

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)