Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker
Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker
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DOI：
10.1002/ijc.24108
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发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Meindl, Alfons
中科院分区：
文献类型：
--
作者：
Sadr-Nabavi, Ariane;Ramser, Juliane;Meindl, Alfons
含有egf的纤维蛋白样细胞外基质蛋白1 （EFEMP1）最近被描述为血管生成的拮抗剂。由于肿瘤生长和转移对血管生成的强烈依赖，我们研究了EFEMP1在人类乳腺癌中的作用。我们对45例散发性乳腺癌组织进行了RNA微阵列表达分析和定量实时PCR （QRT）分析，发现EFEMP1分别在59%和61%的分析组织中下调。这种下调在蛋白水平上得到证实。211例乳腺癌组织的免疫组化结果显示，57-62.5%的肿瘤中EFEMP1表达降低甚至消失。乳腺癌细胞系和原发性乳腺癌组织的亚硫酸盐基因组测序显示，启动子甲基化是这种下调的主要原因。此外，对203例临床特征明确的原发性乳腺癌的分析显示，EFEMP1蛋白表达降低与无病（p = 0.037）和总生存率（p = 0.032）有显著相关性，特别是在接受蒽环类辅助化疗的淋巴结阳性患者中，而在接受环磷酰胺-甲氨蝶呤-5-氟尿嘧啶（CMF）或他莫昔芬治疗的患者中则没有。总之，本文的数据首次证明了EFEMP1在大量散发性乳腺癌中在RNA和蛋白水平上的表达降低及其与表观遗传改变的相关性。此外，这些数据指向EFEMP1表达在原发性乳腺癌中的可能预测作用。(C) 2008 Wiley-Liss, Inc。
EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was recently described as an antagonist of angiogenesis. Motivated by a strong dependence of tumor growth and metastasis on angiogenesis, we investigated the role of EFEMP1 in human breast cancer. We applied RNA microarray expression analysis and quantitative real-time PCR (QRT) in a total of 45 sporadic breast cancer tissues and found EFEMP1 down-regulation in 59% and 61% of the analyzed tissues, respectively. This down-regulation was confirmed on protein level. Immunohistochemistry in 211 breast cancer tissues resulted in reduced or even abolished EFEMP1 expression in 57-62.5% of the tumors. Bisulphite genomic sequencing in breast cancer cell lines and primary breast cancer tissues revealed promoter methylation as the major cause of this down-regulation. Furthermore, analysis of 203 clinically well characterized primary breast cancers displayed a significant correlation of reduced EFEMP1 protein expression with poor disease-free (p = 0.037) and overall survival (p = 0.032), particularly in those node-positive patients who received adjuvant anthracycline-based chemotherapy, but not in those treated by either cyclophosphamide-methotrexate-5-fluorouracil (CMF) or Tamoxifen. In summary, the presented data demonstrate for the first time the reduced EFEMP1 expression on RNA and protein level in a substantial number of sporadic breast carcinomas and its correlation with epigenetic alterations. Furthermore, these data point towards a possible predictive impact of EFEMP1 expression in primary breast cancer. (C) 2008 Wiley-Liss, Inc.