Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity
Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity
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DOI：
10.1038/sj.onc.1206314
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发表时间：
2003-05-01
期刊：
影响因子：
8
通讯作者：
Furth, PA
中科院分区：
文献类型：
--
作者：
Li, ML;Ren, SX;Furth, PA
利用乳清酸性蛋白启动子-T抗原转基因小鼠乳腺癌进展模型，研究了二氟甲基鸟氨酸（DFMO）对乳腺癌发展的化学预防作用的机制。将小鼠暴露于饮食中的四种不同剂量的DFMO（3.5、4.9、7.0和10 g/kg饮食）。肿瘤潜伏期以剂量依赖性方式增加。最高剂量的DFMO显著延迟肿瘤发作（131天，而对照未暴露小鼠为109天，P=0.018）。DFMO治疗后1个月收集的癌前乳腺组织的分析表明，DFMO（10 g/kg饮食）显着增加的凋亡增殖指数的比率（P = 0.013），并显着降低细胞的百分比，显示核定位的细胞周期蛋白D1（P = 0.013）。p27、p21和Stat 5a的核定位不受影响。DFMO对细胞生长和存活的抑制作用随着细胞进展为癌症而丧失。总之，DFMO对乳腺癌进展的化学预防作用是通过癌前细胞凋亡和细胞增殖的变化介导的。癌前细胞中细胞周期蛋白D1活性的改变可以代表化学预防作用的早期生物标志物，并且与细胞周期蛋白D1在乳腺癌进展中的机制作用一致。
Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dose-dependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P=0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P = 0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P = 0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.