17beta-hydroxysteroid dehydrogenase type 1 is an independent prognostic marker in breast cancer.

Estrogens have an important role in the development and progression of breast cancer. 17beta-Hydroxysteroid dehydrogenase type 1 (17HSD1), type 2 (17HSD2), and type 5 (17HSD5) are associated with sex steroid metabolism in normal and cancerous breast tissue. The mRNA expressions of the 17HSD1, 17HSD2, and 17HSD5 enzymes were analyzed in 794 breast carcinoma specimens by using tissue microarrays and normal histologic sections. The results were correlated with the estrogen receptor alpha (ER-alpha) and beta (ER-beta), progesterone receptor, Ki67, and c-erbB-2 expressions analyzed by immunohistochemical techniques and with the Tumor-Node-Metastasis classification, tumor grade, disease-free interval, and survival of the patients. Signals for 17HSD1 mRNA were detected in 16%, 17HSD2 in 25%, and 17HSD5 in 65% of the breast cancer specimens. No association between the 17HSD1, 17HSD2, and 17HSD5 expressions was detected. A significant association was observed between ER-alpha and ER-beta (P = 0.02; odds ratio, 1.96) expressions. There was also a significant inverse association between ER-alpha and 17HSD1 (P = 0.04; odds ratio, 0.53), as well as ER-alpha and 17HSD5 (P = 0.001; odds ratio, 0.35). Patients with tumors expressing 17HSD1 mRNA or protein had significantly shorter overall and disease-free survival than the other patients (P = 0.0010 and 0.0134, log rank). The expression of 17HSD5 was significantly higher in breast tumor specimens than in normal tissue (P = 0.033; odds ratio, 5.56). The group with 17HSD5 overexpression had a worse prognosis than the other patients (P = 0.0146). ER-alpha also associated with survival (P = 0.045). Cox multivariate analyses showed that 17HSD1 mRNA, tumor size, and ER-alpha had independent prognostic significance.

17Beta-hydroxysteroid dehydrogenase type 2: independent prognostic significance and evidence of estrogen protection in female patients with colon cancer.

The mRNA expression of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1 and 2 enzymes catalyzing opposite reaction of estrogen metabolism was investigated in colon cancer. Further, the significance of the 17HSD type 2 enzyme as a possible marker of colorectal cancer (CRC) prognosis was studied. In the normal mucosa, 17HSD type 2 mRNA was predominantly expressed in the surface epithelium and in the upper parts of the crypts. In the lamina propria expression was seen in endothelial cells and mononuclear phagocytes. In colorectal tumors, 17HSD type 2 expression was in most cases downregulated. Female patients had significantly more cancers with high 17HSD type 2 mRNA expression (n=11/35; 31%) than male patients (n=3/39; 8%) (P=0.02). We observed a significant impact of 17HSD type 2 mRNA expression on survival in female patients with distal colorectal cancer (n=24), with an overall cumulative 5-year survival rate of 54% in those with low 17HSD type 2 mRNA expression. None of the female patients with high 17HSD type 2 mRNA expression survived (n=11; P=0.0068; log rank 7.32). In male patients, no significant association with survival was observed. Our data provide evidence suggesting that low 17HSD type 2 mRNA expression is an independent marker of favorable prognosis in females with distal colorectal cancer, supporting the presence of gender- and location-related differences in the pathogenesis of colon cancer.

Sex steroid metabolism in human gastric mucosa: 17 beta-hydroxysteroid dehydrogenase type 2 in normal, inflamed and neoplastic gastric tissues.

The 17 beta-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the regulation of the biological activity of sex steroids. We analyzed the expression of 17HSD type 1 and 2 enzymes which catalyze opposite reactions of estrogen metabolism, in normal gastric mucosa and various gastric diseases of 81 tissue specimens. No expression of 17HSD type 1 mRNA was observed in any of the specimens. 17HSD type 2 mRNA expression was observed in the surface and foveolar epithelium of normal gastric mucosa and in the duodenum, while expression was weak or absent in glandular epithelium. Gender did not have an effect on epithelial expression, but 17HSD type 2 mRNA expression decreased with increasing age in both normal and inflamed gastric mucosa (c = 0.6; p = 0.02, Spearman rank correlation). In children, the expression in glandular epithelium was significantly higher than in adults (p = 0.03). Chronic gastritis was associated with decreased expression in surface epithelium (p = 0.023). Regenerating epithelium close to ulcers and active gastritis showed up-regulation (p < 0.03). Type I intestinal metaplasia showed an up-regulation (p = 0.005) comparable to that seen in the duodenum, while type III metaplasia showed decreased expression in comparison with type I metaplasia (p = 0.003). Expression was further down-regulated in cancer (p < 0.003). 17HSD type 2 mRNA expression in gastric and duodenal epithelium suggests that estrogen and androgen inactivation and active progesterone production are physiological features of gastroduodenal mucosa. The higher 17HSD type 2 mRNA expression in normal gastric mucosa of children compared to adults may be associated with increased need for protection against the mucosal load of foreign substances. The down-regulation associated with aging may have relevance in the pathogenesis of gastric cancer.

Downregulation of estrogen-metabolizing 17 beta-hydroxysteroid dehydrogenase type 2 expression correlates inversely with Ki67 proliferation marker in colon-cancer development.

The 17HSDs are a group of isozymes that catalyze the interconversion between high-activity 17 beta-hydroxysteroids and low-activity 17-ketosteroids. In the present study, we characterized the expression of 17HSD types 1 and 2 in normal and malignant gastrointestinal tissues and cells. Using the colon as a model for cancer of the gastrointestinal tract, expression of the 17HSD enzymes in cancer development was studied and correlated with proliferation and differentiation markers as assessed by Ki67 and mucin staining, respectively. In normal colon and small intestine, 17HSD type 2 mRNA was expressed in the surface epithelial cells and, to a lesser extent, in the cryptal epithelial cells. In colon-cancer specimens, 17HSD type 2 expression was downregulated both in the tissues and in the cell lines and correlated inversely with the proliferation marker. No expression for the 17HSD type 1 enzyme was observed in normal or cancerous gastrointestinal tract tissues. In line with the expression studies, 17HSD activity measurements with colon cells showed that only the oxidative conversion of E2 to E1 was present, and Northern blot analysis showed the signal only for 17HSD type 2. Localization of the ERs alpha and beta, assessed by immunohistochemistry and in situ hybridization, showed the presence of ER beta in the lamina propria of the colon. Our study shows that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. The decrease in expression of the type 2 enzyme may increase estrogen influence in colon cancer.