Gene expression profiling in the mammary gland of rats treated with 7,12-dimethylbenz[a]anthracene
Gene expression profiling in the mammary gland of rats treated with 7,12-dimethylbenz[a]anthracene
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DOI：
10.1002/ijc.21247
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发表时间：
2006-01-01
影响因子：
6.4
通讯作者：
Snyderwine, EG
中科院分区：
文献类型：
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作者：
Papaconstantinou, AD;Shanmugam, I;Snyderwine, EG
早期乳腺癌发生发展的分子标志物的鉴定对于乳腺癌的诊断和预防具有重要意义。在本研究中，我们使用微阵列分析，以检查在大鼠乳腺的基因差异表达后不久，与已知的化学致癌物，7，12-二甲基苯并[a]蒽（DMBA），和肿瘤的发展之前。DMBA后6周，观察到参与细胞生长、分化和微管动力学的多个基因的差异表达。基因表达的变化进一步验证的组合技术，包括实时PCR，RT-PCR，蛋白质印迹和免疫组织化学。DMBA处理的大鼠腺体中P-酪蛋白和转铁蛋白的表达较低，热休克蛋白27的表达较高，提示在此早期阶段抑制分化。细胞周期蛋白D1和热休克蛋白86（一种与细胞周期蛋白D1相关的热休克蛋白）的表达增加表明可能存在细胞周期失调。在肿瘤发生之前，DMBA增加了组织学正常乳腺中Ki-67和stathmin免疫染色检测到的细胞增殖。调节微管功能的基因，包括stathmin，Ran，α-微管蛋白和hsp27，都在DMBA治疗的大鼠乳腺中过表达，提高了微管动力学和异常有丝分裂的破坏可能是乳腺癌发生前的关键事件的可能性。几种改变的蛋白质，包括hsp27，hsp86和stathmin，最终可能成为早期乳腺癌发展的标志物。2005年出版Wiley-Liss，Inc.
Identification of molecular markers of early-stage breast cancer development is important for the diagnosis and prevention of the disease. In the present study, we used microarray analysis to examine the differential expression of genes in the rat mammary gland soon after treatment with a known chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), and prior to tumor development. Six weeks after DMBA, differential expression of multiple genes involved in cell growth, differentiation and microtubule dynamics were observed. Gene expression changes were further validated by a combination of techniques, including real-time PCR, RT-PCR, Western blotting and immunohistochemistry. An inhibition of differentiation in this early stage was suggested by the lower expression of P-casein and transferrin and higher expression of hsp27 in glands from DMBA-treated rats. Possible cell cycle deregulation was indicated by an increased expression of cyclin D1 and hsp86, a heat shock protein associated with cyclin D1. Prior to tumor development, DMBA increased cellular proliferation as detected by Ki-67 and stathmin immunostaining in histologically normal mammary gland. Genes regulating microtubule function, including stathmin, Ran, alpha-tubulin and hsp27, were all overexpressed in the mammary gland of DMBA-treated rats, raising the possibility that disruption of microtubule dynamics and abnormal mitosis may be critical events preceding breast cancer development. Several of the altered proteins, including hsp27, hsp86 and stathmin, may ultimately serve as markers of early breast cancer development. Published 2005 Wiley-Liss, Inc.