Characterization of human BRCA1 heterozygous knockout cell lines created by somatic cell gene targeting

为了评估BRCA1杂合失活在乳腺癌发生中的作用，我们通过在非癌性人类乳腺上皮细胞系中靶向BRCA1基因，创建了BRCA1杂合敲除克隆。这些克隆通过同源重组表现出DNA修复受损，对基因毒性药物过敏，基因组不稳定，但没有表现出转化细胞的特性。这些数据提示BRCA1杂合突变引起的单倍体功能不全并不直接导致细胞转化或肿瘤发展，但可能参与了乳腺癌发生的起始。

To assess the role for heterozygous BRCA1 inactivation in breast carcinogenesis, we created BRCA1 heterozygous knockout clones by targeting the BRCA1 gene in noncanceroushuman breast epithelial cell lines. These clones demonstrated impaired DNA repair via homologous recombination, hypersensitivity to genotoxic agents, and genomic instability, but exhibited no properties of transformed cells. These data suggest that haploinsufficiency caused by BRCA1 heterozygous mutation does not directly lead to cellular transformation or tumor development, but may be involved in the initiation of breast carcinogenesis.