Guzman R C, Osborn R C, Swanson S M, Sakthivel R, Hwang S I, Miyamoto S, Nandi S
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Cancer Res. 1992 Oct 15;52(20):5732-7.
We found previously that mouse mammary epithelial cells cultured in the presence of the mammogenic hormones progesterone and prolactin and treated with the carcinogen N-methyl-N-nitrosourea produced a high frequency of hyperplastic alveolar nodules and carcinomas with squamous metaplasia upon transplantation to syngeneic mice. The majority of these mammary transformants had an activated c-Ki-ras proto-oncogene with a specific point mutation in codon 12 (G35 to A35). To determine whether these in vitro findings parallel mammary carcinogenesis in vivo, virgin female mice were pituitary isografted to increase their circulating levels of progesterone and prolactin. The pituitary isograft results in an increase in proliferation, leading to lobulo-alveolar development and differentiation of the mammary epithelial cells. Five weeks after pituitary isografting, the mice were treated with a single injection of N-methyl-N-nitrosourea (50 micrograms/g body weight). Greater than 90% of the N-methyl-N-nitrosourea-treated mice developed mammary carcinomas between 3 and 7 months after treatment. The majority (75%) of the carcinomas had histopathology identical to that of tumors induced in vitro in the presence of progesterone and prolactin. A number of the mammary cancers (17%) induced in pituitary-isografted mice also had the identical point mutation in the c-Ki-ras proto-oncogene found in the in vitro studies. These results suggest that the hormonal milieu around the time of carcinogen exposure affects not only the incidence and phenotype of the mammary transformants but also the molecular events associated with mammary carcinogenesis.
我们先前发现，在促乳腺激素孕酮和催乳素存在的情况下培养的小鼠乳腺上皮细胞，并用致癌物N-甲基-N-亚硝基脲处理后，移植到同基因小鼠体内会产生高频率的增生性肺泡结节和伴有鳞状化生的癌。这些乳腺转化体中的大多数具有激活的c-Ki-ras原癌基因，其密码子12处有特定的点突变（G35到A35）。为了确定这些体外研究结果是否与体内乳腺致癌作用相似，将未生育的雌性小鼠进行垂体同基因移植，以提高其循环中的孕酮和催乳素水平。垂体同基因移植导致细胞增殖增加，进而导致乳腺上皮细胞的小叶-肺泡发育和分化。垂体同基因移植五周后，给小鼠单次注射N-甲基-N-亚硝基脲（50微克/克体重）。超过90%接受N-甲基-N-亚硝基脲处理的小鼠在处理后3至7个月内发生了乳腺癌。大多数（75%）癌的组织病理学与在孕酮和催乳素存在下体外诱导的肿瘤相同。在垂体同基因移植小鼠中诱导的一些乳腺癌（17%）在c-Ki-ras原癌基因中也有与体外研究中发现的相同点突变。这些结果表明，致癌物暴露时的激素环境不仅影响乳腺转化体的发生率和表型，还影响与乳腺致癌作用相关的分子事件。
