Zhang R, Haag J D, Gould M N
Department of Human Oncology, University of Wisconsin-Madison 53792.
Cancer Res. 1990 Jul 15;50(14):4286-90.
The role of c-Ha-ras-1 oncogene activation in the multistage biological process of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis was investigated. The average yield of NMU-induced mammary tumors in Wistar-Furth rats was altered by modification of either the initiation or promotion/progression stage of carcinogenesis. Initiation was varied by the use of different doses of NMU from 20 to 50 mg/kg. Tumor yield was increased with increasing NMU doses. However, the frequency of mammary tumors with activated c-Ha-ras-1 decreased in a linear fashion with increasing NMU doses. Promotion/progression was varied by increasing prolactin levels starting approximately 2 weeks after NMU administration. This hormonal manipulation increased tumor yield, while reducing the frequency of tumors with activated ras. It is postulated that ras activation represents one of several possible mechanisms by which NMU initiates mammary carcinogenesis. Furthermore, initiated cells without activated ras are more dependent on epigenetic promotional events provided by either prolactin or NMU than are ras-initiated cells.
研究了c-Ha-ras-1癌基因激活在N-甲基-N-亚硝基脲（NMU）诱导的乳腺癌多阶段生物学过程中的作用。通过改变致癌作用的起始阶段或促进/进展阶段，改变了Wistar-Furth大鼠中NMU诱导的乳腺肿瘤的平均产量。通过使用20至50mg/kg的不同剂量的NMU来改变起始阶段。肿瘤产量随着NMU剂量的增加而增加。然而，随着NMU剂量的增加，c-Ha-ras-1激活的乳腺肿瘤频率呈线性下降。通过在NMU给药后约2周开始提高催乳素水平来改变促进/进展阶段。这种激素处理增加了肿瘤产量，同时降低了ras激活的肿瘤频率。据推测，ras激活代表了NMU引发乳腺癌的几种可能机制之一。此外，未激活ras的起始细胞比ras起始的细胞更依赖于催乳素或NMU提供的表观遗传促进事件。
