17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
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DOI：
10.1158/0008-5472.can-08-0821
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Sasano, Hironobu
中科院分区：
文献类型：
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作者：
Nagasaki, Shuji;Suzuki, Takashi;Sasano, Hironobu
17 β-羟基类固醇脱氢酶 12 型 (17 β-HSD12) 已被证明参与极长链脂肪酸 (VLCFA) 的延长以及雌二醇 (E2) 的生物合成。 17β-HSD12 在乳腺癌中也有表达，但其功能仍不清楚。在这项研究中，我们检查了通过微阵列分析确定的 mRNA 表达谱与从 16 例绝经后乳腺癌病例获得的组织 E2 浓度之间的相关性。 17β-HSD12 表达与 E2 浓度之间未检测到显着相关性。然后我们在 110 例浸润性导管癌病例中对这种酶进行了免疫定位。乳腺癌细胞中的17β-HSD12免疫反应性与患者的不良预后显着相关。我们使用基于细胞的研究进一步检验了 17 beta-HSD12 的生物学意义。在 SK-BR-3（雌激素受体阴性乳腺癌细胞系）中，小干扰 RNA 介导的 17 beta-HSD12 敲低导致显着的生长抑制，通过添加花生四烯酸等 VLCFA 可以恢复这种抑制。 17β-HSD12 免疫反应性状态也与环氧合酶 2 (COX2) 阳性乳腺癌患者的不良临床结果相关，但与 COX2 阴性患者无关。因此，这些研究结果表明，至少在人类乳腺癌中，17-HSD12不一定与肿瘤内E2生物合成相关，而是与VLCFA（例如花生四烯酸）的产生相关，这些VLCFA随后可能通过COX2代谢为前列腺素并导致患者的肿瘤进展。 [癌症研究 2009;69(4):1392-9]
17 beta-Hydroxysteroid dehydrogenase type 12 (17 beta-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17 beta-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 17 beta-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17 beta-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17 beta-HSD12 using cell-based studies. Small interfering RNA-mediated knockdown of 17 beta-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 17 beta-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 17 -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 he metabolized to prostaglandins by COX2 and result in tumor progression of the patients. [Cancer Res 2009;69(4):1392-9]