Wijnhoven Susan W P, Zwart Edwin, Speksnijder Ewoud N, Beems Rudolf B, Olive Kenneth P, Tuveson David A, Jonkers Jos, Schaap Mirjam M, van den Berg Jolanda, Jacks Tyler, van Steeg Harry, de Vries Annemieke
Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Cancer Res. 2005 Sep 15;65(18):8166-73. doi: 10.1158/0008-5472.CAN-05-1650.
The tumor suppressor gene p53 has an apparent role in breast tumor development in humans, as approximately 30% of sporadic tumors acquire p53 mutations and Li-Fraumeni syndrome patients carrying germ line p53 mutations frequently develop breast tumors at early age. In the present study, conditional expression of a targeted mutation is used to analyze the role of the human R273H tumor-associated hotspot mutation in p53 in mammary gland tumorigenesis. Heterozygous p53(R270H/+)WAPCre mice (with mammary gland-specific expression of the p53.R270H mutation, equivalent to human R273H, at physiologic levels) develop mammary tumors at high frequency, indicating that the R270H mutation predisposes for mammary gland tumor development and acts in a dominant-negative manner in early stages of tumorigenesis. Spontaneous tumor development in these mice is further accelerated by 7,12-dimethylbenz(a)anthracene (DMBA) treatment at young age. The majority of spontaneous and DMBA-induced carcinomas and sarcomas from p53(R270H/+)WAPCre mice is estrogen receptor alpha positive, and expression profiles of genes also implicated in human breast cancer appear similarly altered. As such, p53(R270H/+)WAPCre mice provide a well-suited model system to study the role of p53 in breast tumorigenesis and the responsiveness of mammary gland tumors to chemotherapeutics.
肿瘤抑制基因p53在人类乳腺肿瘤发生过程中具有明显作用，因为大约30%的散发性肿瘤会发生p53突变，而且携带p53种系突变的李-佛美尼综合征患者经常在早年就发生乳腺肿瘤。在本研究中，通过条件性表达靶向突变来分析p53中人类R273H肿瘤相关热点突变在乳腺肿瘤发生中的作用。杂合的p53(R270H/+)WAPCre小鼠（在生理水平下乳腺特异性表达p53.R270H突变，等同于人类R273H）高频发生乳腺肿瘤，这表明R270H突变易导致乳腺肿瘤发生，并在肿瘤发生的早期以显性负性方式起作用。幼年时用7,12-二甲基苯并(a)蒽（DMBA）处理可进一步加速这些小鼠的自发肿瘤发生。来自p53(R270H/+)WAPCre小鼠的大多数自发和DMBA诱导的癌和肉瘤雌激素受体α呈阳性，并且与人类乳腺癌相关的基因表达谱也出现类似改变。因此，p53(R270H/+)WAPCre小鼠提供了一个非常合适的模型系统，用于研究p53在乳腺肿瘤发生中的作用以及乳腺肿瘤对化疗药物的反应性。
