15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer
15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer
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DOI：
10.1158/0008-5472.can-05-4368
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
--
作者：
Wolf, Ido;O'Kelly, James;Koeffler, H. Phillip
前列腺素E-2在乳腺癌中起着生长刺激作用，其合成中的限速酶环加氧酶-2在这些癌症中经常过表达。前列腺素分解代谢关键酶15-羟前列腺素脱氢酶（15-PGDH）在乳腺癌发病机制中的作用知之甚少。使用基于药理学的表观遗传学沉默基因筛选，我们发现MDA-MB-231细胞[雌激素受体（ER）阴性]中15-PGDH水平较低，但MCF-7细胞（ER阳性）中15-PGDH水平较高，并观察到其在脱甲基后上调处理。进一步的分析显示，在一个乳腺癌细胞系和30%的原发性肿瘤中15-PGDH启动子甲基化。15-PGDH表达分析显示40%的原发性乳腺肿瘤中15-PGDH表达水平较低，并确定了15-PGDH和ER表达之间的相关性。转染实验表明，瞬时上调MDA-MB-231细胞中15-PGDH水平导致克隆生长下降，稳定上调显著降低这些细胞在裸鼠体内形成肿瘤的能力。相反，MCF-7细胞中15-PGDH的瞬时沉默导致其增殖增强，并且这些细胞中的稳定沉默增强体外细胞周期进入和体内致瘤性。15-PGDH的强制表达抑制ER途径，15-PGDH的沉默上调芳香化酶的表达。此外，15-PGDH水平下调雌激素，但上调的肿瘤抑制基因CAAT/增强子结合蛋白α。我们的研究结果首次表明，15-PGDH可能是一种新的乳腺癌抑癌基因，并表明这种酶可以调节ER通路。
Prostaglandin E-2 plays a growth-stimulatory role in breast cancer, and the rate-limiting enzyme in its synthesis, cyclo-oxygenase-2, is often overexpressed in these cancers. Little is known about the role of the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in breast cancer pathogenesis. Using a pharmacologically based screen for epigenetically silenced genes, we found low levels of 15-PGDH in MDA-MB-231 cells [estrogen receptor (ER) negative] but high levels in MCF-7 cells (ER positive) and observed its up-regulation following demethylation treatment. Further analysis revealed methylation of the 15-PGDH promoter in one breast cancer cell line and 30% of primary tumors. Analysis of 15-PGDH expression revealed low levels in 40% of primary breast tumors and identified a correlation between 15-PGDH and ER expression. Transfection assays showed that transient up-regulation of 15-PGDH levels in MDA-MB-231 cells resulted in a decreased clonal growth, and stable up-regulation significantly decreased the ability of these cells to form tumors in athymic mice. In contrast, transient silencing of 15-PGDH in MCF-7 cells resulted in their enhanced proliferation, and a stable silencing in these cells enhanced cell cycle entry in vitro and tumorigenicity in vivo. Forced expression of 15-PGDH inhibited the ER pathway and silencing of 15-PGDH up-regulated expression of aromatase. In addition, 15-PGDH levels were down-regulated by estrogen but up-regulated by the tumor suppressor gene CAAT/enhancer binding protein alpha. Our results indicate for the first time that 15-PGDH may be a novel tumor suppressor gene in breast cancer, and suggest that this enzyme can modulate the ER pathway.