Lu S J, Archer M C
Department of Medical Biophysics, University of Toronto, ON, Canada.
Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1001-5. doi: 10.1073/pnas.89.3.1001.
A single dose of N-methyl-N-nitrosourea given to sexually immature female Buf/N rats produces a high incidence of mammary adenocarcinomas. A large percentage of these tumors contain the Ha-ras oncogene, activated by a G----A transition at the second nucleotide of codon 12. Copenhagen rats, on the other hand, are completely resistant to mammary tumor induction by a number of carcinogens, including N-methyl-N-nitrosourea. Here we show, using a sensitive method involving PCR, that codon 12 Ha-ras mutations occur in the mammary glands of both Buf/N and Copenhagen rats 30 days after N-methyl-N-nitrosourea treatment. These mutations were evenly distributed among individual mammary glands and were present in purified mammary epithelial cells. In Buf/N rats, the fraction of cells containing a mutated Ha-ras allele increased by a factor of 10-100 between 30 and 60 days, whereas in Copenhagen rats, there was no such increase during this time period. We conclude that the resistance of the Copenhagen rat to mammary carcinogenesis is not due to a defect in initiation but rather appears to be due to the inability of cells containing a mutated ras allele to undergo sustained clonal expansion.
给性未成熟的雌性Buf/N大鼠单次注射N-甲基-N-亚硝基脲会导致乳腺腺癌的高发病率。这些肿瘤中有很大比例含有Ha-ras癌基因，该基因通过密码子12第二个核苷酸处的G→A转换而被激活。另一方面，哥本哈根大鼠对包括N-甲基-N-亚硝基脲在内的多种致癌物诱导的乳腺肿瘤完全具有抗性。在这里，我们使用一种涉及PCR的灵敏方法表明，在N-甲基-N-亚硝基脲处理30天后，Buf/N大鼠和哥本哈根大鼠的乳腺中均出现了密码子12的Ha-ras突变。这些突变在各个乳腺中均匀分布，并且存在于纯化的乳腺上皮细胞中。在Buf/N大鼠中，含有突变型Ha-ras等位基因的细胞比例在30至60天之间增加了10到100倍，而在哥本哈根大鼠中，在此时间段内没有这种增加。我们得出结论，哥本哈根大鼠对乳腺致癌作用的抗性不是由于启动缺陷，而是似乎由于含有突变型ras等位基因的细胞无法进行持续的克隆扩增。
