Parous mammary glands exhibit distinct alterations in gene expression and proliferation responsiveness to carcinogenic stimuli in Lewis rats.
Parous mammary glands exhibit distinct alterations in gene expression and proliferation responsiveness to carcinogenic stimuli in Lewis rats.
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DOI：
10.3892/or.15.4.903
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发表时间：
2006-04
期刊：
影响因子：
4.2
通讯作者：
N. Uehara;A. Unami;Y. Kiyozuka;N. Shikata;Y. Oishi;A. Tsubura
中科院分区：
文献类型：
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作者：
N. Uehara;A. Unami;Y. Kiyozuka;N. Shikata;Y. Oishi;A. Tsubura
早期足月妊娠可提供终身保护，防止乳腺癌的发展。产次诱导的保护作用可以在致癌物诱导的大鼠乳腺癌模型中重现，但这种保护作用对大鼠乳腺中致癌刺激的分子机制尚未完全表征。为了更好地了解这些分子机制，我们使用寡核苷酸芯片检测致癌剂（N-甲基-N-亚硝基脲; MNU）治疗前后刘易斯大鼠经产和年龄匹配的处女（AMV）乳腺中的基因表达。MNU处理前的经产乳腺显示出多个分化相关基因的上调，如乳清酸性蛋白（Wap）、酪蛋白β（Csn 2）、酪蛋白γ（Csng）、脂多糖结合蛋白（Lbp）、分泌型磷蛋白1（Spp 1）和糖基化依赖性细胞粘附分子1（Glycam 1）。此外，MNU治疗前的经产乳腺表现出生长相关基因的下调，如再生胰岛衍生3 α（Reg 3a）、间皮素（Msln）、胰岛素样生长因子2（Igf 2）和胰岛素样生长因子结合蛋白4（Igfbp 4）。MNU处理后，AMV乳腺表现出生长相关基因的上调，如Msln，细胞分裂周期2同源物A（Cdc 2a），Igf 2，Igfbp 4，stathmin 1（Stmn 1）和同源框，msh样1（Msx 1），而这些基因的表达在经产乳腺中仍然较低。AMV乳腺也表现出显着上调Cdc 2a和Stmn 1响应MNU。经MNU处理后，AMV乳腺上皮细胞的PCNA标记指数显著增加（13.7+/-1.1%），但在经产乳腺中保持较低（3.6+/-0.4%）。AMV乳腺对致癌刺激的反应包括生长相关基因的上调和细胞增殖的增加。在经产乳腺中缺乏类似的反应可以解释产次诱导的对乳腺肿瘤发展的保护。
Early full-term pregnancy affords lifetime protection against the development of breast cancer. Parity-induced protection can be reproduced in a carcinogen-induced rat mammary carcinoma model, but the molecular mechanisms of this protection against carcinogenic stimuli in rat mammary glands have not been fully characterized. To gain a better understanding of these molecular mechanisms, we used an oligonucleotide microarray to examine gene expression in parous and age-matched virgin (AMV) mammary glands of Lewis rats before and after carcinogen (N-methyl-N-nitrosourea; MNU) treatment. Parous mammary glands before MNU treatment showed up-regulation of multiple differentiation-related genes, such as whey acidic protein (Wap), casein beta (Csn2), casein gamma (Csng), lipopolysaccharide binding protein (Lbp), secreted phosphoprotein 1 (Spp1) and glycosylation-dependent cell adhesion molecule 1 (Glycam1). Also, parous mammary glands before MNU treatment exhibited down-regulation of growth-related genes such as regenerating islet-derived 3 alpha (Reg3a), mesothelin (Msln), insulin-like growth factor 2 (Igf2) and insulin-like growth factor binding protein 4 (Igfbp4). After MNU treatment, AMV mammary glands exhibited up-regulation of growth-related genes, such as Msln, cell division cycle 2 homolog A (Cdc2a), Igf2, Igfbp4, stathmin 1 (Stmn1) and homeobox, msh-like 1 (Msx1), whereas expression of these genes remained low in parous mammary glands. AMV mammary glands also exhibited marked up-regulation of Cdc2a and Stmn1 in response to MNU. After MNU treatment, the PCNA labeling index increased significantly in AMV mammary epithelial cells (13.7+/-1.1%), but remained low in parous mammary glands (3.6+/-0.4%). The response of AMV mammary glands to carcinogenic stimuli includes up-regulation of growth-related genes and increased cell proliferation. The lack of a similar response in parous mammary glands may explain parity-induced protection against mammary tumor development.