Tumor formation in Brca1 conditional mutant mice
Tumor formation in Brca1 conditional mutant mice
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DOI：
10.1002/em.10069
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发表时间：
2002-01-01
影响因子：
2.8
通讯作者：
Deng, CX
中科院分区：
文献类型：
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作者：
Deng, CX
BRCA 1是第一个乳腺癌相关基因，其突变使女性易患乳腺癌和卵巢癌。小鼠中Brca 1的靶向突变导致胚胎死亡，主要归因于细胞增殖缺陷，这引发了关于Brca 1抑制肿瘤形成的机制的问题。为了克服早期致死性，我们通过在其外显子11两侧插入loxP位点来改造Brca 1。我们发现，缺失外显子的EIIA-Cre，表达Cre的生殖细胞系，导致p53依赖性致死在妊娠晚期。另一方面，在乳腺上皮中表达Cre的MMTV-Cre在长潜伏期后导致低频率的肿瘤发生，伴随上皮细胞凋亡增加和异常导管发育。在p53（+/-）遗传背景下，乳腺肿瘤的形成显著加速;然而，它仍然以随机的方式出现，表明涉及其他因素。值得注意的是，肿瘤在组织病理学上高度多样，并显示出广泛的遗传/分子改变，包括ErbB 2，c-Myc，p27和Cyclin D1的过表达，以及大多数肿瘤中p16的下调。这一观察结果表明这些蛋白在Brca 1相关肿瘤发生中的作用。出版2002 Wiley-Liss，Inc.
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. Published 2002 Wiley-Liss, Inc.