Estrogen receptor β deficiency enhances small intestinal tumorigenesis in ApcMin/+ mice
Estrogen receptor β deficiency enhances small intestinal tumorigenesis in ApcMin/+ mice
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DOI：
10.1002/ijc.23532
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发表时间：
2008-07-15
影响因子：
6.4
通讯作者：
Carrier, Julie C.
中科院分区：
文献类型：
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作者：
Giroux, Veronique;Lemay, Frederic;Carrier, Julie C.
临床证据表明，雌二醇替代疗法可降低绝经后妇女患结肠癌的风险。在结肠上皮细胞中，雌激素受体β（ER β）是主要的ER亚型，并被认为介导雌激素的基因组效应。本研究的第一个目的是研究在猿小鼠模型中ER β缺乏对肠道肿瘤发生的后果。此外，为了探索雌激素可能影响结直肠癌发病机制的生物学机制，我们在卵巢切除野生型（WT）与ER β（-/-）小鼠的结肠细胞中进行了基因表达谱分析，这些小鼠用雌二醇（E（2））或载体治疗。特别是在女性中，发现ER β缺乏与小肠中较高的腺瘤多样性相关，但与结肠中的腺瘤多样性无关。此外，ER β（-/-）Apc（Min/+）雌性小鼠的肿瘤平均显著大于对照Apc（Min/+）小鼠的肿瘤。通过BrdU掺入试验证实，ER β（-/-）Apc（Min/+）雌性小鼠与Ape（Min/+）雌性小鼠的空肠和结肠上皮细胞稳态增殖较高。有趣的是，微阵列结果的功能分类揭示了TGF β信号传导途径在结肠细胞中被调节，特别是对于WT + E（2）与WT +媒介物和ER β（-/-）+ E（2）与WT + E（2）的比较。使用定量PCR分析，我们观察到TGF β途径配体的转录物在E（2）处理的WT和ER β（-/-）小鼠的结肠细胞中上调，而在ER β缺陷小鼠中下调，主要是以E（2）非依赖性方式。因此，我们的研究结果表明，ER β缺乏增强小肠肿瘤的发生，并表明TGF β信号通路的调制可能有助于雌激素对肠道肿瘤发生的保护作用。(C)2008 Wiley-Liss，Inc.
Clinical evidence suggests that estradiol replacement therapy reduces colon cancer risk in 'post'menopausal women. In colon epithelial cells, the estrogen receptor beta (ER beta) is the predominant ER subtype and is thought to mediate the genomic effect of estrogens. The first aim of this study was to investigate the consequence of ER beta deficiency on intestinal tumorigenesis in the Ape mouse model. Furthermore, to explore the biological mechanisms by which estrogens may influence the pathogenesis of colorectal cancer, we performed gene expression profiles in colonocytes from ovariectomized wild-type (WT) vs. ER beta(-/-) mice, treated with estradiol (E(2)) or vehicle. Specifically in female, ER beta deficiency was found to be associated with higher adenoma multiplicity in the small intestine, but not in the colon. Furthermore, tumors from ER beta(-/-) Apc(Min/+) female mice were on average significantly larger than those from control Apc(Min/+) mice. Higher steady-state proliferation in epithelial cells of the jejunum and colon from ER beta(-/-)Apc(Min/+) vs. Ape(Min/+) female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGF beta signaling pathway to be modulated in colonocytes, especially for the WT + E(2) VS. WT + Vehicle and the ER beta(-/-) + E(2) VS. WT + E(2) comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGF beta pathway to be upregulated in colonocytes from E(2)-treated WT and ER beta(-/-) mice and downregulated in ER beta-deficient mice, mostly in an E(2)-independent manner. Therefore, our results demonstrate that ER beta deficiency enhances small intestinal tumorigenesis and suggest that modulation of the TGF beta signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis. (C) 2008 Wiley-Liss, Inc.