SASH1:: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer
SASH1:: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer
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DOI：
10.1038/sj.onc.1206474
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发表时间：
2003-05-15
期刊：
影响因子：
8
通讯作者：
Scherneck, S
中科院分区：
文献类型：
--
作者：
Zeller, C;Hinzmann, B;Scherneck, S
应用杂合性缺失（LOH）和硅表达分析来鉴定乳腺癌基因组区间6q23-25内显著下调的基因。将候选EST序列与该区间的基因组序列进行系统比较，揭示了6q24.3上一个潜在靶基因的基因组结构，我们称之为SAM和SH3结构域I （SASH1）。在30%的原发性乳腺癌中发现的基因内部标记物D6S311的缺失与生存率低和肿瘤大小增加显著相关。存在两个SASH1转录本，分别约4.4和7.5 kb，主要在人类乳腺、肺、甲状腺、脾脏、胎盘和胸腺中转录。在乳腺癌细胞期，SASH1仅在低水平表达。与相应的正常乳腺上皮组织相比，SASH1在大多数（74%）乳腺肿瘤中下调。此外，SASH1在肺和甲状腺肿瘤中也下调。蛋白质结构域的分析表明，SASH1是最近描述的SH3/SAM适配器分子家族的成员，因此提示在信号通路中起作用。我们认为SASH1是一种新的肿瘤抑制基因，可能参与了乳腺癌和其他实体癌的肿瘤发生。我们无法在原发性乳腺癌的基因编码区发现突变，在关键区域显示LOH。因此，我们假设其他机制，如SASH1启动子区域的甲基化，是导致原发性和转移性乳腺癌中SASH1表达缺失的原因。
Loss of heterozygosity (LOH) and in silico expression analysis were applied to identify genes significantly downregulated in breast cancer within the genomic interval 6q23-25. Systematic comparison of candidate EST sequences with genomic sequences from this interval revealed the genomic structure of a potential target gene on 6q24.3, which we called SAM and SH3 domain containing I (SASH1). Loss of the gene-internal marker D6S311, found in 30% of primary breast cancer, was significantly correlated with poor survival and increase in tumor size. Two SASH1 transcripts of approximately 4.4 and 7.5 kb exist and are predominantly transcribed in the human breast, lung, thyroid, spleen, placenta and thymus. In breast cancer cell tines, SASH1 is only expressed at low levels. SASH1 is downregulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelial tissues. In addition, SASH1 is also downregulated in tumors of the lung and thyroid. Analysis of the protein domain structure revealed that SASH1 is a member of a recently described family of SH3/SAM adapter molecules and thus suggests a role in signaling pathways. We assume that SASH1 is a new tumor suppressor gene possibly involved in tumorigenesis of breast and other solid cancers. We were unable to find mutations in the coding region of the gene in primary breast cancers showing LOH within the critical region. We therefore hypothesize that other mechanisms as for instance methylation of the promoter region of SASH1 are responsible for the loss of expression of SASH1 in primary and metastatic breast cancer.