Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors
Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors
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DOI：
10.1080/01926230500352226
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发表时间：
2005-01-01
影响因子：
1.5
通讯作者：
Seldin, DC
中科院分区：
文献类型：
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作者：
Currier, N;Solomon, SE;Seldin, DC
只有大约5%的人类乳腺癌可以归因于乳腺癌易感基因的遗传，而其余的被认为是散发性的起源。乳腺癌的发病率随饮食和其他环境影响而变化，包括致癌物暴露。然而，环境致癌物对细胞生长控制途径的影响知之甚少。在这里，我们研究了致癌信号通路，在乳腺肿瘤中激活的小鼠与原型多环芳烃（PAH）7，12-二甲基苯并[a]蒽（DMBA）。在雌性FVB小鼠中，从5周龄开始每周管饲给予6剂1 mg DMBA，所有小鼠在34周龄时（开始DMBA后中位数20周）均发生肿瘤; 75%的小鼠患有乳腺肿瘤。DMBA诱导的乳腺肿瘤表现出芳香烃受体（AhR），c-myc，细胞周期蛋白D1和过度磷酸化视网膜母细胞瘤（Rb）蛋白的表达升高。因此，评估了上游调节途径的激活，发现与正常乳腺对照相比，Wnt信号传导途径、NF-κ B途径和脯氨酰异构酶Pin-1的元件在肿瘤中频繁上调。这些数据表明，环境致癌物可以产生长期的生长和抗凋亡途径的改变，导致乳腺肿瘤的发生。
Only about 5% of human breast cancers can be attributed to inheritance of breast cancer susceptibility genes, while the balance are considered to be sporadic in origin. Breast cancer incidence varies with diet and other environmental influences, including carcinogen exposure. However, the effects of environmental carcinogens on cell growth control pathways are poorly understood. Here we have examined oncogenic signaling pathways that are activated in mammary tumors in mice treated with the prototypical polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). In female FVB mice given 6 doses of 1 mg of DMBA by weekly gavage beginning at 5 weeks of age, all of the mice developed tumors by 34 weeks of age (median 20 weeks after beginning DMBA); 75% of the mice had mammary tumors. DMBA-induced mammary tumors exhibited elevated expression of the aryl hydrocarbon receptor (AhR), c-myc, cyclin D1, and hyperphosphorylated retinoblastoma (Rb) protein. Because of this, the activation of upstream regulatory pathways was assessed, and elements of the Wnt signaling pathway, the NF-kappa B pathway, and the prolyl isomerase Pin-1 were found to be frequently up-regulated in the tumors when compared to normal mammary gland controls. These data suggest that environmental carcinogens can produce long-lasting alterations in growth and anti-apoptotic pathways, leading to mammary tumorigenesis.