Abstract
17beta-Hydroxysteroid dehydrogenase type 12 (17beta-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17beta-HSD12 expression was also reported in breast carcinomas but its functions have remained unknown. In this study, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases. No significant correlations were detected between 17beta-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17beta-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17beta-HSD12 using cell-based studies. Small interfering RNA-mediated knockdown of 17beta-HSD12 in SK-BR-3 (estrogen receptor-negative breast carcinoma cell line) resulted in significant growth inhibition, which was recovered by the addition of VLCFAs such as arachidonic acid. The status of 17beta-HSD12 immunoreactivity was also correlated with adverse clinical outcome in cyclooxygenase 2 (COX2)-positive breast cancer patients but not in COX2-negative patients. Therefore, these findings indicated that 17beta-HSD12 was not necessarily related to intratumoral E2 biosynthesis, at least in human breast carcinoma, but was rather correlated with production of VLCFAs such as arachidonic acid, which may subsequently be metabolized to prostaglandins by COX2 and result in tumor progression of the patients.
Highlights
The 17h-hydroxysteroid dehydrogenases (17h-HSD) are the key enzymes that catalyze the reversible interconversions between biologically active and inactive sex steroids [1]
The abundance of 17h-HSD 1 and CYP19A1 mRNA tended to be positively correlated with tissue E2 levels but the 17h-HSD12 mRNA was by no means associated with the levels of tissue E2 concentration
We examined the effect of 17h-HSD12 expression in the survival of the patient in correlation with cyclooxygenase 2 (COX2) status, which has been reported as the main enzyme converting arachidonic acid (AA) to prostaglandins and subsequently stimulates cancer progression, based on the result of cell proliferation assay in which AA is considered the key fatty acid synthesized via the pathway including 17h-HSD12
Summary
The 17h-hydroxysteroid dehydrogenases (17h-HSD) are the key enzymes that catalyze the reversible interconversions between biologically active and inactive sex steroids [1]. Fourteen isozymes of 17h-HSD have been identified and some of these isozymes have been reported to be involved in the pathogenesis or development of. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Requests for reprints: Hironobu Sasano, Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagiken 980-8575, Japan. Phone: 81-22-717-8050; Fax: 81-22-717-8051; E-mail: hsasano@ patholo2.med.tohoku.ac.jp. One of the most fully characterized 17h-HSDs is type 1 (17h-HSD1), which catalyzes the conversion of weak estrone (E1) to the more potent estradiol (E2) and proposed to be involved in breast carcinoma development via E2 biosynthesis [4]. Some of these isozymes have been shown to have diverse substrate preferences not restricted to steroids [5]
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