Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene
Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene
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DOI：
10.1038/sj.onc.1204505
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发表时间：
2001-06-28
期刊：
影响因子：
8
通讯作者：
Shen, CY
中科院分区：
文献类型：
--
作者：
Cheng, CW;Wu, PE;Shen, CY
杂合性缺失（LOH）允许肿瘤抑制基因（TSG）的隐性突变表达，因此，基于Knudson关于TSG失活的“双击”假说，在染色体区域检测高LOH频率被认为是TSG定位的关键。乳腺癌中的LOH区域之一是16q22.1，这被认为反映了e -钙粘蛋白（E-cad）的参与，e -钙粘蛋白是一种细胞间的粘附分子。为了确认Ecad的致瘤作用，我们对81例乳腺散发的侵袭性导管癌（IDCs）进行了检测，以确定灭活该基因所需的“两次命中”。在67个信息性肿瘤中检测到高频率（37.3%）的LOH，但未发现突变。为了研究转录机制在LOH肿瘤中作为第二次打击的可能性，确定了特定途径，包括启动子区域的遗传变异和超甲基化以及阳性（WT1）和阴性（Snail）转录因子的异常表达。其中，启动子超甲基化和Snail表达增加被发现是常见的（> 35%），并且与E-cad表达减少/阴性密切相关(P
Loss of heterozygosity (LOH) allows the expression of recessive mutation in tumor suppressor genes (TSG), Therefore, on the basis of Knudson's 'two-hit' hypothesis for TSG inactivation, the detection of a high LOH frequency in a chromosomal region is considered critical for TSG localization. One of these LOH regions in breast cancer is 16q22.1, which has been suggested to reflect the involvement of E-cadherin (E-cad), a cell-tell adhesion molecule, To confirm the tumorigenic role of Ecad, 81 sporadic invasive ductal carcinomas (IDCs) of the breast were tested for the 'two hits' required to inactivate this gene. A high frequency (37.3%) of LOH was detected in 67 informative tumors, but no mutation was found. To examine the possibility that transcriptional mechanisms serve as the second hit in tumors with LOH, specific pathways, including genetic variant and hypermethylation at the promoter region and abnormal expression of positive (WT1) and negative (Snail) transcription factors, were identified. Of these, promoter hypermethylation and increased expression of Snail were found to be common (> 35%), and to be strongly associated with reduced/negative E-cad expression (P