Journal
MOLECULAR ONCOLOGY
Volume 8, Issue 7, Pages 1326-1338Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2014.04.009
Keywords
FEN1; Breast cancer; Prognostic factor; Predictive factor; Drug target
Categories
Funding
- NIH grant [1 R03 MH092154-01]
- Intramural Research Program of the National Institute on Aging, NIH
- Molecular Libraries Common Fund Program of the NIH
- National Center for Advancing Translational Sciences (USA)
- University of Nottingham and Nottingham University Hospitals Charity (UK)
- Medical Research Council, UK
- Cancer Research UK [16942] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10154, ACF-2009-12-003, CL-2010-12-003] Funding Source: researchfish
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FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 x 10(-57)), high mitotic index (p = 5.25 x 10(-28)), pleomorphism (p = 6.31 x 10(-19)), ER negative (p = 9.02 x 10(-35)), PR negative (p = 9.24 x 10(-24)), triple negative phenotype (p = 6.67 x 10(-21)), PAM50.Her2 (p = 5.19 x 10(-13)), PAM50. Basal (p = 2.7 x 10(-41)), PAM50.LumB (p = 1.56 x 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 x 10(-12)), intClust.5 (p = 4.05 x 10(-12)) and intClust. 10 (p = 7.59 x 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 x 10(-16)) and multivariate analysis (p = 9.19 x 10(-7)). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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