Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma
Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma
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DOI：
10.1128/mcb.23.7.2225-2238.2003
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发表时间：
2003-04-01
影响因子：
5.3
通讯作者：
Fusco, A
中科院分区：
文献类型：
--
作者：
Baldassarre, G;Battista, S;Fusco, A
BRCA1基因表达的急剧减少是侵袭性散发性乳腺癌的特征。然而，乳腺癌中BRCA1下调的潜在机制还不清楚。在这里，我们报告，在体外和体内HMGA1b蛋白结合，并抑制人类和小鼠BRCA1启动子的活性。一致的是，小鼠胚胎干细胞（ES）与Hmga 1基因删除显示更高的Brca 1的mRNA和蛋白质水平比野生型ES细胞。用HMGA1b cDNA稳定转染MCF-7细胞导致BRCA 1基因表达减少，并且在雌激素处理后缺乏BRCA 1诱导。最后，我们发现HMGA 1和BRCA 1的mRNA和蛋白在人乳腺癌细胞系和组织中的表达呈负相关。这些数据表明，HMGA 1蛋白参与BRCA 1基因的转录调控，其过表达可能在侵袭性乳腺癌中观察到的BRCA 1下调中发挥作用。
A drastic reduction in BRCA1 gene expression is a characteristic feature of aggressive sporadic breast carcinoma. However, the mechanisms underlying BRCA1 downregulation in breast cancer are not well understood. Here we report that both in vitro and in vivo HMGA1b protein binds to and inhibits the activity of both human and mouse BRCA1 promoters. Consistently, murine embryonic stem (ES) cells with the Hmga1 gene deleted display higher Brca1 mRNA and protein levels than do wild-type ES cells. Stable transfection of MCF-7 cells with the HMGA1b cDNA results in a decrease of BRCA1 gene expression and in a lack of BRCA1 induction after estrogen treatment. Finally, we found an inverse correlation between HMGA1 and BRCA1 mRNA and protein expression in human mammary carcinoma cell lines and tissues. These data indicate that HMGA1 proteins are involved in transcriptional regulation of the BRCA1 gene, and their overexpression may have a role in BRCA1 downregulation observed in aggressive mammary carcinomas.