Overexpression of 17β-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17β-estradiol

J Clin Endocrinol Metab. 2012 Apr;97(4):E591-601. doi: 10.1210/jc.2011-2994. Epub 2012 Feb 22.

Abstract

Context: 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.

Patients and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cell Line, Tumor
  • Cell Proliferation
  • Endometrial Neoplasms / enzymology*
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology
  • Endometrium / enzymology*
  • Endometrium / metabolism
  • Endometrium / pathology
  • Estradiol / metabolism*
  • Estradiol Dehydrogenases / genetics
  • Estradiol Dehydrogenases / metabolism*
  • Estrogen Receptor alpha / metabolism
  • Estrone / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oxidation-Reduction
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Tissue Culture Techniques

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Isoenzymes
  • Neoplasm Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Estrone
  • Estradiol
  • Estradiol Dehydrogenases
  • HSD17B1 protein, human