Andres A C, Bchini O, Schubaur B, Dolder B, LeMeur M, Gerlinger P
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Strasbourg, France.
Oncogene. 1991 May;6(5):771-9.
The promoter of the mammary specific murine whey acidic protein gene was used to direct Ha-ras expression in different lines of transgenic mice. We found that this promoter contains a tissue specific enhancer which directed expression in both orientations albeit to different levels. We used this feature to generate low and high ras expressing transgenic lines. The reversed orientation led to a weak expression in lines 3 and 58 and to a tumor frequency of 2%. In contrast, 72% of mice from line 25 showing high ras expression developed mammary tumors. Nulliparity is one risk factor for human breast cancer, suggesting a protective effect of post-lactational mammary regression. In order to investigate the effect of post-lactational regression, the low tumor frequency lines were crossed with mice expressing ubiquitously the human growth hormone gene, which induces permanent development of the mammary epithelium. Indeed, mammary tumors were observed in 76% of double transgenic females. Thus, the tumorigenic potential of the ras oncogene in mammary cells in vivo correlates with the level of its expression and with the developmental history of the mammary gland. Transformation coincides with the escape of oncogene expression from the regulation of the Wap promoter and the extinction of endogenous Wap gene expression.
利用乳腺特异性小鼠乳清酸性蛋白基因的启动子在不同品系的转基因小鼠中指导Ha-ras表达。我们发现该启动子含有一个组织特异性增强子，其在两个方向上均能指导表达，尽管表达水平不同。我们利用这一特性构建了低表达和高表达ras的转基因品系。反向定向导致3号线和58号线表达较弱，肿瘤发生率为2%。相比之下，25号线中显示高ras表达的小鼠有72%发生了乳腺肿瘤。未生育是人类乳腺癌的一个风险因素，提示哺乳期后乳腺退化具有保护作用。为了研究哺乳期后退化的影响，将低肿瘤发生率品系与普遍表达人生长激素基因的小鼠杂交，该基因可诱导乳腺上皮的持续发育。实际上，在76%的双转基因雌性小鼠中观察到了乳腺肿瘤。因此，ras癌基因在体内乳腺细胞中的致瘤潜力与其表达水平以及乳腺的发育史相关。转化与癌基因表达从Wap启动子的调控中逃逸以及内源性Wap基因表达的消失同时发生。
