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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
Author(s) -
SadrNabavi 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
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24108
Subject(s) - breast cancer , cancer research , dna methylation , biology , methylation , angiogenesis , cancer , epigenetics , breast disease , methyltransferase , bisulfite sequencing , pathology , medicine , gene expression , gene , genetics
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. © 2008 Wiley‐Liss, Inc.