title: Overexpression of 17β-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17β-estradiol.
abstract: BACKGROUND
  The local interconversions between estrone (low activity) and 17β-estradiol (potent compound) by 17β-hydroxysteroid dehydrogenases (17β-HSDs) can lead to high 17β-estradiol generation in endometrial cancer (EC).
  
  
  OBJECTIVE
  Examine the balance between the 17β-HSDs reducing estrone to 17β-estradiol (types 1, 5, 12, and 7) and those oxidizing 17β-estradiol to estrone (2, 4, and 8), in EC.
  
  
  METHODS
  Reducing and oxidizing 17β-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/17β-estradiol oxidation balance in favor of 17β-estradiol compared with controls. This was more pronounced among estrogen receptor-α (ER-α)-positive biopsies. Type 1 17β-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-α-positive grade 1 EC than controls. The mRNA coding for types 4, 5, 7, 8, and 12 17β-HSD did not vary, whereas that coding for type 2 17β-HSD was increased in high-grade lesions compared with controls. Three-dimensional ex vivo EC explant cultures demonstrated that 17β-HSD type 1 generated 17β-estradiol from estrone and increased tumor cell proliferation. Additional in vitro studies using EC cells confirmed that in the presence of 17β-HSD type 1, estrone induced estrogen signaling activation similarly to 17β-estradiol. Therefore, estrone was reduced to 17β-estradiol.
  
  
  CONCLUSIONS
  Type 1 17β-HSD increases 17β-estradiol exposure in grade 1 EC, thus supporting tumor growth. This enzyme represents a potential therapeutic target.
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands.
authors.forename: Karlijn M C
authors.initials: KM
authors.lastname: Cornel
authors.forename: Roy F P M
authors.initials: RF
authors.lastname: Kruitwagen
authors.forename: Bert
authors.initials: B
authors.lastname: Delvoux
authors.forename: Laura
authors.initials: L
authors.lastname: Visconti
authors.forename: Koen K
authors.initials: KK
authors.lastname: Van de Vijver
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Toon
authors.initials: T
authors.lastname: Van Gorp
authors.forename: Rob J J
authors.initials: RJ
authors.lastname: Hermans
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Dunselman
authors.forename: Andrea
authors.initials: A
authors.lastname: Romano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000378:metabolism*; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D046509:Tissue Culture Techniques
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004970:Estrone; D004958:Estradiol; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human