BRCA1和BRCA2基因缺陷的小鼠模型:过去的经验教训、当前的认识及未来展望。
Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.
作者信息
Evers B, Jonkers J
机构信息
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
出版信息
Oncogene. 2006 Sep 25;25(43):5885-97. doi: 10.1038/sj.onc.1209871.
Germline mutations in BRCA1 and BRCA2 are responsible for a large proportion of hereditary breast and ovarian cancers. Soon after the identification of both genes in the mid-1990s, investigators set out to develop mouse models for the associated disease. Whereas conventional Brca1 and Brca2 mouse mutants did not reveal a strong phenotype in a heterozygous setting, most homozygous mutations caused embryonic lethality. Consequently, development of mouse models for BRCA-associated tumorigenesis required the generation of tissue-specific conditional knockout animals. In this review, we give an overview of the conventional and the conditional mouse models of BRCA1 and BRCA2 deficiency generated over the last decade, as well as the contribution of these models to our understanding of the biological and molecular functions of BRCA1 and BRCA2. The most advanced mouse models for BRCA1- and BRCA2-associated tumorigenesis mimic human disease to the extent that they can be used in studies addressing clinically relevant questions. These models will help to resolve yet unanswered questions and to translate our increasing knowledge of BRCA1 and BRCA2 biology into clinical practice.
BRCA1和BRCA2的种系突变是导致大部分遗传性乳腺癌和卵巢癌的原因。20世纪90年代中期这两个基因被鉴定出来后不久,研究人员就着手开发相关疾病的小鼠模型。尽管传统的Brca1和Brca2小鼠突变体在杂合状态下并未表现出强烈的表型,但大多数纯合突变会导致胚胎致死。因此,开发与BRCA相关的肿瘤发生的小鼠模型需要生成组织特异性条件性敲除动物。在这篇综述中,我们概述了过去十年中产生的BRCA1和BRCA2缺陷的传统和条件性小鼠模型,以及这些模型对我们理解BRCA1和BRCA2的生物学和分子功能的贡献。用于BRCA1和BRCA2相关肿瘤发生的最先进的小鼠模型在一定程度上模拟了人类疾病,可用于解决临床相关问题的研究。这些模型将有助于解决尚未解答的问题,并将我们对BRCA1和BRCA2生物学不断增加的认识转化为临床实践。