Qiu Cunping, Shan Liang, Yu Minshu, Snyderwine Elizabeth G
Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Health of Institutes, Bethesda, Maryland 20892-4262, USA.
Cancer Res. 2003 Sep 15;63(18):5674-8.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a suspected human breast carcinogen found in cooked meat that induces mammary gland cancer in rats. By real time PCR analysis, PhIP-induced rat mammary gland carcinomas showed statistically higher expression of the G(1)-S cyclin D1 (5-fold) and its kinase partner cyclin-dependent kinase (Cdk)-4 (37-fold) in comparison with normal mammary gland, whereas cyclin D2, cyclin D3, and Cdk6 were not statistically changed. Amplification of cyclin D1 was observed by real time PCR in 24% of carcinomas (15 of 63). Only 1 of 47 carcinomas showed Cdk4 amplification. By Western blotting, the level of phospho-Rb was >2-fold higher in carcinomas than in normal mammary gland. By immunohistochemical analysis, cyclin D1, Cdk4, and phospho-Rb nuclear protein expression was 5.7-, 3.9-, and 2.3-fold higher, respectively, in carcinomas than in normal mammary gland, whereas the expression of cyclin D2, cyclin D3, and Cdk6 was similar. Among carcinomas, Cdk4 and phospho-Rb levels were positively correlated with cell proliferation. Previous studies by this laboratory indicated that these carcinomas harbor a high frequency of H-ras mutations. The H-ras pathway is linked to the cell cycle via cyclin D1. The results from the current study implicate cyclin D1/Cdk4, phospho-Rb as a central pathway in PhIP-induced rat mammary gland carcinogenesis.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是一种在熟肉中发现的疑似人类乳腺癌致癌物，可诱发大鼠乳腺癌。通过实时PCR分析，与正常乳腺相比，PhIP诱导的大鼠乳腺癌中G(1)-S细胞周期蛋白D1（5倍）及其激酶伴侣细胞周期蛋白依赖性激酶（Cdk）-4（37倍）的表达在统计学上显著更高，而细胞周期蛋白D2、细胞周期蛋白D3和Cdk6在统计学上没有变化。通过实时PCR在24%的癌组织（63个中的15个）中观察到细胞周期蛋白D1的扩增。47个癌组织中只有1个显示Cdk4扩增。通过蛋白质印迹法，癌组织中磷酸化Rb的水平比正常乳腺高2倍以上。通过免疫组织化学分析，癌组织中细胞周期蛋白D1、Cdk4和磷酸化Rb核蛋白的表达分别比正常乳腺高5.7倍、3.9倍和2.3倍，而细胞周期蛋白D2、细胞周期蛋白D3和Cdk6的表达相似。在癌组织中，Cdk4和磷酸化Rb水平与细胞增殖呈正相关。该实验室先前的研究表明，这些癌组织中H-ras突变的频率很高。H-ras途径通过细胞周期蛋白D1与细胞周期相连。当前研究的结果表明细胞周期蛋白D1/Cdk4、磷酸化Rb是PhIP诱导的大鼠乳腺癌发生中的核心途径。
