17β-hydroxysteroid dehydrogenase types 1 and 2 in human normal and malignant breast and gastrointestinal tract
1University of Oulu, Faculty of Medicine, Research Center for Molecular Endocrinology
2University of Oulu, Faculty of Medicine, WHO Collaborating Centre for Research on Reproductive Health
3University of Oulu, Biocenter Oulu
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|Persistent link:|| http://urn.fi/urn:isbn:9514270746
|Publish Date:|| 2003-07-02
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium 9 of the University Hospital of Oulu, on July 2nd, 2003, at 12 noon.
Docent Antti Pajunen
Professor Matti Poutanen
17β-hydroxysteroid dehydrogenases (17HSDs) catalyze the interconversion of high-activity 17β-hydroxysteroids and low-activity 17-ketosteroids. In the present study, the mRNA of the 17HSD type 1 and 2 enzymes, catalyzing opposite reactions of estrogen metabolism, was analyzed in normal and malignant breast and gastrointestinal tract by in situ hybridization. Further, the activities of these enzymes were measured in normal and adenomatous intestinal cell lines. Markers of the main mesenchymal cell types were also used to study the cell-type specific expression of the 17HSD type 2 enzyme in the gastrointestinal tract.
The mRNA of the 17HSD types 1 and 2 was expressed in normal breast tissues of premenopausal, but not postmenopausal women. In breast cancer, varied mRNA expressions of the enzymes were seen in both groups of women. Variable mRNA expressions of the reductive 17HSD type 5 enzyme were also seen in breast cancer tissues. Patients with tumors expressing 17HSD type 1 mRNA had significantly shorter overall survival and disease-free interval than those without 17HSD type 1 expression, suggesting that inhibition of the enzyme may be beneficial in the prevention or treatment of hormone-dependent breast cancers.
In normal gastric tissues, 17HSD type 2 mRNA was expressed mainly in the surface and foveolar epithelium. Expression was weak or absent in glandular epithelium. Gender did not have any effect on expression, but there was a decrease with increasing age. Chronic gastritis was associated with decreased expression, while upregulation was observed in intestinal metaplasia. In gastric malignancy, downregulation was observed in most specimens.
17HSD type 2 mRNA was expressed mainly in absorptive epithelia cells and the upper parts of crypts in normal intestinal tissues. In the lamina propria, expression was detected in endothelial cells and mononuclear phagocytes. In colon cancer, the enzyme was downregulated in most, but not all cases. 17HSD type 1 and 2 activity measurements in normal and colon cancer cell lines showed a predominant oxidative activity. Northern analysis also revealed the transcript for the 17HSD type 2 enzyme.
Female subjects had significantly more colon cancers with high 17HSD type 2 mRNA than males; however, low 17HSD type 2 mRNA expression was associated with survival in females with cancer of the distal colon and rectum. These data indicate the presence of gender- and location-related differences in the pathogenesis of colon cancer and suggest that low 17HSD type 2 mRNA expression is a marker of a favorable prognosis.
Acta Universitatis Ouluensis. D, Medica
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