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17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis

¹ Department of Pathology, ² Department of Pathology and Histotechnology; ³ Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁴ Kawasaki Research Center, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan; ⁵ Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan; and ⁶ Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan

Requests for reprints: Hironobu Sasano, Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan. Phone: 81-22-717-8050; Fax: 81-22-717-8051; E-mail: hsasano{at}patholo2.med.tohoku.ac.jp.

Key Words: breast cancer • fatty acid • estrogen • 17β–hydroxysteroid dehydrogenase type 12

17β-Hydroxysteroid dehydrogenase type 12 (17β-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17β-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 17β-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17β-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17β-HSD12 using cell-based studies. Small interfering RNA–mediated knockdown of 17β-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 17β-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 17β-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. [Cancer Res 2009;69(4):1392–9]