CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer.
DNA microarrays have the potential to classify tumors according to their transcriptome. Tissue microarrays (TMAs) facilitate the validation of biomarkers by offering a high-throughput approach to sample analysis. We reanalyzed a high profile breast cancer DNA microarray dataset containing 96 tumor samples using a powerful statistical approach, between group analyses. Among the genes we identified was centromere protein-F (CENP-F), a gene associated with poor prognosis. In a published follow-up breast cancer DNA microarray study, comprising 295 tumour samples, we found that CENP-F upregulation was significantly associated with worse overall survival (p<0.001) and reduced metastasis-free survival (p<0.001). To validate and expand upon these findings, we used 2 independent breast cancer patient cohorts represented on TMAs. CENP-F protein expression was evaluated by immunohistochemistry in 91 primary breast cancer samples from cohort I and 289 samples from cohort II. CENP-F correlated with markers of aggressive tumor behavior including ER negativity and high tumor grade. In cohort I, CENP-F was significantly associated with markers of CIN including cyclin E, increased telomerase activity, c-Myc amplification and aneuploidy. In cohort II, CENP-F correlated with VEGFR2, phosphorylated Ets-2 and Ki67, and in multivariate analysis, was an independent predictor of worse breast cancer-specific survival (p=0.036) and overall survival (p=0.040). In conclusion, we identified CENP-F as a biomarker associated with poor outcome in breast cancer and showed several novel associations of biological significance.
O'Brien
Sallyann L
SL
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Fagan
Ailís
A
Fox
Edward J P
EJ
Millikan
Robert C
RC
Culhane
Aedín C
AC
Brennan
Donal J
DJ
McCann
Amanda H
AH
Hegarty
Shauna
S
Moyna
Siobhan
S
Duffy
Michael J
MJ
Higgins
Desmond G
DG
Jirström
Karin
K
Landberg
Göran
G
Gallagher
William M
WM
D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002503:Centromere / Q000502:physiology; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008207:Lymphatic Metastasis; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011379:Prognosis; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015996:Survival Rate; D046888:Tissue Array Analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D050787:Proto-Oncogene Protein c-ets-2; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; C094772:centromere protein F; D040301:Vascular Endothelial Growth Factor Receptor-2