High frequency of hypermethylation at the 14-3-3 σ locus leads to gene silencing in breast cancer
High frequency of hypermethylation at the 14-3-3 σ locus leads to gene silencing in breast cancer
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DOI：
10.1073/pnas.100566997
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发表时间：
2000-05-23
影响因子：
11.1
通讯作者：
Sukumar, S
中科院分区：
文献类型：
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作者：
Ferguson, AT;Evron, E;Sukumar, S
14-3-3 sigma （sigma）在DNA损伤时被诱导表达，并在G中引起细胞阻滞(2)。通过SAGE（基因表达序列分析）分析，我们发现sigma基因在乳腺癌细胞中的表达比在正常乳腺上皮细胞中的表达低7倍。我们通过Northern blot分析验证了这一发现。值得注意的是，48例原发性乳腺癌中有45例未检测到sigma mRNA。sigma基因的遗传改变如杂合性缺失是罕见的（1/20信息性病例），未检测到突变（0/34）。另一方面，在91%（75/82）的乳腺肿瘤中检测到sigma基因CpG岛的高甲基化，并与基因表达缺乏相关。因为用药物5-aza-2'-脱氧胞苷治疗不表达sigma的乳腺癌细胞系导致基因的去甲基化和mRNA的合成。缺乏sigma表达的乳腺癌细胞在暴露于γ辐照时显示出更多的染色体断裂和间隙，因此，sigma表达的缺失可能通过损害G(2)细胞周期检查点功能而导致恶性转化，从而导致遗传缺陷的积累。到目前为止，高甲基化和sigma表达缺失是乳腺癌中最一致的分子改变。
Expression of 14-3-3 sigma (sigma) is induced in response to DNA damage, and causes cells to arrest in G(2), By SAGE (serial analysis of gene expression) analysis, we identified sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, sigma mRNA was undetectable in 45 of 48 primary breast carcinomas. Genetic alterations at sigma such as loss of heterozygosity were rare (1/20 informative cases), and no mutations were detected (0/34), On the other hand, hypermethylation of CpG islands in the sigma gene was detected in 91% (75/82) of breast tumors and was associated with lack of gene expression, Hypermethylation of sigma is functionally important, because treatment of sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of a mRNA. Breast cancer cells lacking sigma expression showed increased number of chromosomal breaks and gaps when exposed to gamma-irradiation, Therefore, it is possible that loss of sigma expression contributes to malignant transformation by impairing the G(2) cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Hypermethylation and loss of sigma expression are the most consistent molecular alterations in breast cancer identified so far.