Cha R S, Thilly W G, Zarbl H
Division of Toxicology, Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge 02139.
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3749-53. doi: 10.1073/pnas.91.9.3749.
GGA to GAA mutations in the 12th codon of the Hras gene are frequently observed in rat mammary tumors induced by N-nitroso-N-methylurea (NMU). We developed an assay to measure point mutations present in tissues at a frequency of 10(-5) and have now applied this assay to measure the specific G to A transition of the Hras gene in rat mammary epithelium. We find that (i) 70% of untreated rats contain detectable levels of Hras mutants; (ii) these mutants are clustered within the gland as sectors in a manner consistent with their origin as a mutation arising during early organ development; and (iii) treatment with a carcinogenic dose of NMU did not result in a significant increase in the number of such mutants, the fraction of organ sectors with mutant cells, or the fraction of animals containing detectable levels of ras mutants. We conclude that the NMU-induced mammary tumors carrying the G to A transition at the 12th codon of the Hras gene arose from preexisting ras mutants and that an independent effect of NMU was directly or indirectly responsible for tumor formation.
在由N-亚硝基-N-甲基脲（NMU）诱导的大鼠乳腺肿瘤中，经常观察到Hras基因第12密码子处的GGA到GAA突变。我们开发了一种检测方法，用于测量组织中频率为10^(-5)的点突变，现在已应用该方法来测量大鼠乳腺上皮中Hras基因特定的G到A转变。我们发现：（i）70%的未处理大鼠含有可检测水平的Hras突变体；（ii）这些突变体以与它们起源于早期器官发育过程中产生的突变一致的方式，作为区段聚集在腺体中；（iii）用致癌剂量的NMU处理并未导致此类突变体数量、含有突变细胞的器官区段比例或含有可检测水平ras突变体的动物比例显著增加。我们得出结论，携带Hras基因第12密码子处G到A转变的NMU诱导的乳腺肿瘤起源于预先存在的ras突变体，并且NMU的独立作用直接或间接导致了肿瘤形成。
