Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer
Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer
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DOI：
10.1172/jci36640
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Zarnegar, Reza
中科院分区：
文献类型：
--
作者：
Ma, Jihong;DeFrances, Marie C.;Zarnegar, Reza
HGF基因在正常分化的乳腺上皮细胞中转录沉默，但它的抑制在乳腺癌组织和细胞系中不能发生。HGF在乳腺癌细胞中异常表达的分子机制尚不清楚。在此，我们报道了位于人HGF启动子转录起始点上游750个碱基的DNA元件的发现，该元件在人乳腺癌细胞和组织中作为转录抑制物和缺失突变的靶标。该HGF启动子元件由30个脱氧腺苷(30A)的单核苷酸重复序列组成，我们称之为“脱氧腺苷束元件”(DATE)。功能研究表明，DATE内的截断突变通过调节染色质结构和DNA-蛋白质相互作用，对HGF启动子区域产生深刻的局部和整体影响，导致HGF启动子在人乳腺癌细胞系中的结构性激活。我们发现，51%的非裔美国人和15%的患有乳腺癌的欧洲混合血统的人在他们的乳腺肿瘤中存在截断的日期变异(25As或更少)，并且截断的等位基因与癌症发病率和HGF异常表达有关。值得注意的是，带有截短日期变异的乳腺癌患者比那些携带野生型基因的乳腺癌患者要年轻得多。我们还建议，DATE可以作为一个潜在的遗传标记来识别患乳腺癌风险较高的个人。
The HGF gene is transcriptionally silenced in normal differentiated breast epithelial cells, but its repression fails to occur in mammary carcinoma tissues and cell lines. The molecular mechanisms underpinning aberrant HGF expression in breast cancer cells are unknown. Here we report the discovery of a DNA element located 750 bp upstream from the transcription start site in the human HGF promoter that acts as a transcriptional repressor and is a target of deletion mutagenesis in human breast cancer cells and tissues. This HGF promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which we have termed "deoxyadenosine tract element" (DATE). Functional studies revealed that truncation mutations within DATE have profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter in human breast carcinoma cell lines. We found that 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a truncated DATE variant (25As or fewer) in their breast tumors and that the truncated allele is associated with cancer incidence and aberrant HGF expression. Notably, breast cancer patients with the truncated DATE variant are substantially younger than those with a wild-type genotype. We also suggest that DATE may be used as a potential genetic marker to identify individuals with a higher risk of developing breast cancer.