Mechanisms of egfr gene transcription modulation:: Relationship to cancer risk and therapy response
Mechanisms of egfr gene transcription modulation:: Relationship to cancer risk and therapy response
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DOI：
10.1158/1078-0432.ccr-06-0626
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发表时间：
2006-12-15
影响因子：
11.5
通讯作者：
Buerger, Horst
中科院分区：
文献类型：
--
作者：
Brandt, Burkhard;Meyer-Staeckling, Soenke;Buerger, Horst
表皮生长因子受体（EGFR）在正常细胞和癌细胞的生长、分化和运动中起着至关重要的作用。对于癌症的预测性诊断和EGFR的治疗靶向，了解EGFR的表达水平是如何被控制的以及与受体信号传导的关系是很重要的。已经描述了一种新的转录调控机制，该机制依赖于EGFR基因内含子1中的CA重复序列[CA简单序列重复1 (CA SSR I)]的长度。因此，CA重复数与pre-mRNA合成呈负相关。间接证据表明这一机制的重要性，包括在该序列中含有短CA重复序列的癌症组织中优先发生扩增，以及在具有该疾病家族史的年轻乳腺癌患者和日本乳腺癌患者中发现不同的等位基因。可以假设CA重复序列的长度影响DNA的可弯曲性，从而影响抑制蛋白的结合。总之，CA SSR I似乎代表了抗egfr治疗反应的遗传变量，可以在治疗前确定。此外，还应研究其与其他多态性（如EGFR R497K （HER-1 497K）和CCND1 A870G）协同作用的可能性，从而同时增加EGFR信号活性和表达。从实际的角度来看，评估CA SSR I的CA clinucleotide重复数作为临床结果的预测因子是非常有吸引力的，因为它是一个不变的特征，不随时间变化，可以很容易地在正常和癌症组织（血细胞，皮肤和肿瘤活检）中进行测量，技术上简单，客观，甚至定量。
The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation, and motility of normal as well as cancer cells. For predictive cancer diagnostics and therapeutic targeting of EGFR, it is important to know how the expression level of EGFR is controlled and related to receptor signaling. A novel transcriptional regulation mechanism has been described that depends on the length of a CA repeat in intron 1 [CA simple sequence repeat 1 (CA SSR I)] of the EGFR gene. Thereby, the number of CA repeats is inversely correlated to pre-mRNA synthesis. Indirect evidence for the importance of this mechanism includes the preferential occurrence of amplifications in cancer tissue harboring short CA repeats in this sequence and the discovery of distinct alleles in young breast cancer patients with a family history of the disease and in Japanese breast cancer patients. It can be postulated that the length of the CA repeat influences DNA bendability and, in consequence, the binding of repressor proteins. In summary, it seems that the CA SSR I represents an inherited variable for response to anti-EGFR therapies that could be determined before therapy. Moreover, the potential for synergistic effects with other polymorphism [e.g., EGFR R497K (HER-1 497K) and CCND1 A870G] leading to a simultaneous increase of EGFR signaling activity and expression should be investigated. From a practical perspective, assessment of the CA SSR I number of CA clinucleotide repeats as a predictor for clinical outcome is very attractive because it is a constant feature that does not change over time and can be easily measured in normal and cancer tissues (blood cells, skin, and tumor biopsies) in an assay that is technically simple, objective, and even quantitative.