Deng Chu-Xia
Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Environ Mol Mutagen. 2002;39(2-3):171-7. doi: 10.1002/em.10069.
BRCA1 is the first breast cancer-associated gene, whose mutation predisposes women to breast and ovarian cancers. Targeted mutations of Brca1 in the mouse result in embryonic lethality primarily attributed to cellular proliferation defects, raising questions about the mechanisms by which Brca1 represses tumor formation. To overcome the early lethality, we engineered Brca1 by flanking its exon 11 with loxP sites. We showed that deletion of the exon by EIIA-Cre, which expresses Cre in the germline, causes p53-dependent lethality at late gestation. On the other hand, MMTV-Cre, which expresses Cre in mammary epithelium, resulted in tumorigenesis at low frequency after a long latency, accompanied by increased epithelial cell apoptosis and abnormal ductal development. Mammary tumor formation was significantly accelerated in a p53(+/-) genetic background; however, it still appeared in a stochastic fashion, suggesting the involvement of additional factors. Notably, the tumors were highly diverse in histopathology and displayed extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27, and Cyclin D1, and downregulation of p16 in the majority of tumors. This observation suggests roles for these proteins in Brca1-associated tumorigenesis.
BRCA1是首个被发现的与乳腺癌相关的基因，其突变会使女性易患乳腺癌和卵巢癌。在小鼠中对Brca1进行靶向突变会导致胚胎致死，这主要归因于细胞增殖缺陷，这引发了关于Brca1抑制肿瘤形成机制的疑问。为了克服早期致死问题，我们通过在其第11外显子两侧添加loxP位点来改造Brca1。我们发现，由EIIA-Cre（在生殖系中表达Cre）介导的第11外显子缺失会在妊娠后期导致p53依赖性致死。另一方面，在乳腺上皮中表达Cre的MMTV-Cre，经过长时间潜伏期后会以低频率导致肿瘤发生，同时伴有上皮细胞凋亡增加和导管发育异常。在p53(+/-)遗传背景下，乳腺肿瘤形成显著加速；然而，肿瘤仍以随机方式出现，这表明还有其他因素参与其中。值得注意的是，这些肿瘤在组织病理学上高度多样，并表现出广泛的基因/分子改变，包括大多数肿瘤中ErbB2、c-Myc、p27和细胞周期蛋白D1的过表达以及p16的下调。这一观察结果表明这些蛋白质在Brca1相关的肿瘤发生中发挥作用。
