Buerger Horst, Packeisen Jens, Boecker Almuth, Tidow Nicola, Kersting Christian, Bielawski Krzysztof, Isola Jorma, Yatabe Yasushi, Nakachi Kei, Boecker Werner, Brandt Burkhard
Institute of Pathology, University of Münster, Albert-Schweitzer-Strasse 33, 48139 Münster, Germany.
J Pathol. 2004 May;203(1):545-50. doi: 10.1002/path.1542.
Overexpression of the epidermal growth factor receptor (EGFR) is a common finding in invasive breast cancer and represents a potential target for new treatment options. However, little is known about the parameters that might indicate a potential clinical response for these anti-EGFR-based therapies. In order to gain further insights into the interplay between the length of a CA-SSR I repeat in intron 1 of egfr, copy numbers of this untranslated regulatory sequence, and protein expression, the present study investigated breast cancers from Germans and Japanese patients by microsatellite analysis, quantitative 5' nuclease assay by egfr enzyme-linked immunosorbent assay (ELISA), and comparative genomic hybridization (CGH). Japanese breast cancer patients displayed significantly longer alleles for the CA-SSR I repeat (p < 0.001), associated with significantly lower EGFR expression (mean 65 versus 36 fmol/mg membrane protein). Allelic imbalance (restricted to CA-SSR I) was observed in 55% of the informative Japanese breast cancers compared with only 34% of the German breast cancer reference group. Using a quantitative 5' nuclease assay for egfr, a significantly higher percentage of Japanese breast cancer patients revealed amplifications of the CA-SSR I repeat (p < 0.01). Japanese patients with these amplifications were characterized by a significantly higher EGFR content compared with the German breast cancer patients (p < 0.05). These data show, on the one hand, that the correlation of EGFR overexpression and an inherited CA repeat polymorphism within intron 1 of egfr is a general finding in breast cancer, as has been shown previously. On the other hand, the data demonstrate clearly for the first time an interaction between the length of a polymorphism in intron 1 of egfr as an inherited genetic factor and the frequency of egfr amplification, as an acquired genetic factor, both factors contributing to EGFR overexpression in breast cancer. This new knowledge about mechanisms of regulation of EGFR expression might serve as an additional basis for evaluating anti-EGFR-based therapies.
表皮生长因子受体（EGFR）的过表达在浸润性乳腺癌中很常见，是新治疗方案的潜在靶点。然而，对于可能表明这些基于抗EGFR疗法具有潜在临床反应的参数，人们了解甚少。为了进一步深入了解egfr基因内含子1中CA-SSR I重复序列的长度、该非翻译调控序列的拷贝数与蛋白表达之间的相互作用，本研究通过微卫星分析、egfr酶联免疫吸附测定（ELISA）的定量5'核酸酶测定以及比较基因组杂交（CGH），对德国和日本患者的乳腺癌进行了研究。日本乳腺癌患者的CA-SSR I重复序列等位基因明显更长（p < 0.001），且与EGFR表达显著降低相关（平均分别为65和36 fmol/mg膜蛋白）。在55%的可提供信息的日本乳腺癌中观察到等位基因失衡（仅限于CA-SSR I），而德国乳腺癌参照组中这一比例仅为34%。使用针对egfr的定量5'核酸酶测定，发现日本乳腺癌患者中CA-SSR I重复序列扩增的比例显著更高（p < 0.01）。与德国乳腺癌患者相比，具有这些扩增的日本患者的EGFR含量显著更高（p < 0.05）。这些数据一方面表明，EGFR过表达与egfr基因内含子1中遗传性CA重复多态性之间的相关性是乳腺癌中的普遍现象，正如之前所显示的那样。另一方面，这些数据首次清楚地证明了egfr基因内含子1中作为遗传因素的多态性长度与作为获得性遗传因素的egfr扩增频率之间的相互作用，这两个因素都导致了乳腺癌中EGFR的过表达。关于EGFR表达调控机制的这一新知识可能为评估基于抗EGFR的疗法提供额外依据。
