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

作者：Sadr Nabavi Ariane; Ramser Juliane; Volkmann Juliane; Naehrig Joerg; Wiesmann Frank; Betz Beate; Hellebrand Heide; Engert Stefanie; Seitz Susanne; Kreutzfeld Rene; Sasaki Takako; Arnold Norbert; Schmutzler Rita; Kiechle Marion; Niederacher Dieter; Harbeck Nadia; Dahl Edgar; Meindl Alfons^*

来源：International Journal of Cancer, 2009, 124(7): 1727-1735.

DOI：10.1002/ijc.24108

• breast cancer
• EFEMP1
• angiogenesis
• promoter methylation
• molecular marker

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.

• 出版日期2009-4-1