Mei Jianxun, Hu Hongbo, McEntee Michael, Plummer Howard, Song Ping, Wang Hwa-Chain R
Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA.
Breast Cancer Res Treat. 2003 May;79(1):95-105. doi: 10.1023/a:1023326121951.
Repeated treatments of non-cancerous human breast epithelial cells MCF10A with a low dose of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced the development of cancerous cells. NNK-transformed MCF10A cells acquired cancerous properties including anchorage-independent cell growth and increased cell motility. Cellular transformation of MCF10A cells was accompanied by a loss of responsiveness to 17beta-estradiol and decreased rate of cell proliferation. NNK-transformed MCF10A cells were also tumorigenic in immunodifficient mice. Studies of changes in the regulation of intracellular signaling pathways revealed that the upstream Erk pathway was down-regulated in the NNK-transformed cells. Our data provide the first evidence suggesting that the tobacco carcinogen NNK is competent to induce malignant transformation of non-cancerous human breast epithelial cells. Our findings suggest that the tobacco carcinogen NNK may contribute to early events in human breast carcinogenesis.
用低剂量的烟草特异性致癌物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)反复处理非癌性人乳腺上皮细胞MCF10A可诱导癌细胞的产生。NNK转化的MCF10A细胞获得了癌细胞特性，包括不依赖贴壁的细胞生长和细胞运动性增加。MCF10A细胞的细胞转化伴随着对17β-雌二醇反应性的丧失和细胞增殖速率的降低。NNK转化的MCF10A细胞在免疫缺陷小鼠中也具有致瘤性。对细胞内信号通路调控变化的研究表明，在NNK转化的细胞中上游Erk通路被下调。我们的数据提供了首个证据，表明烟草致癌物NNK能够诱导非癌性人乳腺上皮细胞发生恶性转化。我们的研究结果表明，烟草致癌物NNK可能在人类乳腺癌发生的早期事件中起作用。
