Asamoto Makoto, Ota Tomonori, Toriyama-Baba Hiroyasu, Hokaiwado Naomi, Naito Akihiro, Tsuda Hiroyuki
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Jpn J Cancer Res. 2002 Jan;93(1):32-5. doi: 10.1111/j.1349-7006.2002.tb01197.x.
We have previously shown that transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are highly susceptible to N-methyl-N-nitrosourea (MNU) mammary carcinogenesis. All transgenic rats treated with 50 mg / kg MNU, i.v. at 50 days of age, were found to rapidly develop multiple, large mammary carcinomas within as short a period as 8 weeks. In the present study, the effects of ovariectomy and treatment with d-limonene, known to inhibit mammary carcinogenesis in non-transgenic female rats, were investigated in Hras128 animals treated with MNU to clarify the role of the human c-Ha-ras proto-oncogene and to characterize the induced mammary carcinomas. Although ovariectomy completely inhibited development of mammary carcinomas in their wild-type counterparts, it did not affect either the incidence or the multiplicity of the mammary carcinomas in the Hras128 rats. On the other hand, treatment with d-limonene, an inhibitor of ras protein isoprenylation, inhibited the breast tumor development. These results indicate that aberrant c-Ha-ras gene expression is involved in ovarian hormone-independent growth and c-Ha-ras protein isoprenylation plays an important role in mammary carcinogenesis.
我们之前已经表明，携带三个拷贝人类c-Ha-ras原癌基因（Hras128）的转基因大鼠对N-甲基-N-亚硝基脲（MNU）诱导的乳腺癌发生高度敏感。所有在50日龄时静脉注射50 mg / kg MNU的转基因大鼠，在短短8周内就迅速长出多个大的乳腺癌。在本研究中，我们在接受MNU处理的Hras128动物中研究了卵巢切除术和用d-柠檬烯处理的效果，已知d-柠檬烯可抑制非转基因雌性大鼠的乳腺癌发生，以阐明人类c-Ha-ras原癌基因的作用并对诱导的乳腺癌进行特征描述。虽然卵巢切除术完全抑制了其野生型对照中乳腺癌的发生，但它对Hras128大鼠中乳腺癌的发生率或多发性均无影响。另一方面，用d-柠檬烯（一种ras蛋白异戊二烯化抑制剂）处理可抑制乳腺肿瘤的发展。这些结果表明，异常的c-Ha-ras基因表达参与了不依赖卵巢激素的生长，并且c-Ha-ras蛋白异戊二烯化在乳腺癌发生中起重要作用。
