title: CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer.
abstract: 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.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Sallyann L
authors.initials: SL
authors.lastname: O'Brien
authors.forename: Ailís
authors.initials: A
authors.lastname: Fagan
authors.forename: Edward J P
authors.initials: EJ
authors.lastname: Fox
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Aedín C
authors.initials: AC
authors.lastname: Culhane
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Amanda H
authors.initials: AH
authors.lastname: McCann
authors.forename: Shauna
authors.initials: S
authors.lastname: Hegarty
authors.forename: Siobhan
authors.initials: S
authors.lastname: Moyna
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Higgins
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
mesh_terms: 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
chemical_list: 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