Carcinogenesis Advance Access published online on November 21, 2003
Carcinogenesis, doi:10.1093/carcin/bgh019
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Oncology & Pathology, Radiumhemmet, Karolinska Hospital & Institute, Stockholm, Sweden
* Corresponding author. E-mail: thomas.lindahl{at}cck.ki.se.
Received 9 July 2003
; revised 24 October 2003
; accepted 28 October 2003
Cyclin E is one of the key regulators of the G1/S transition in the cell cycle. Overexpression of cyclin E has been observed in several malignancies and is associated with high proliferation, aberrant expression of other cell cycle regulators and chromosomal instability in vitro. To explore potential associations between cyclin E deregulation and inactivation of the p53 tumor suppressor gene in human breast cancer, we investigated the immunohistochemical (IHC) expression of cyclin E in paraffin embedded breast cancers from 270 women with known p53 status by cDNA based sequencing of the p53 gene. The breast cancers were divided into three subgroups according to the percentage of cyclin E positive cells. One hundred and seventy-one patients (63%) had low cyclin E, 72 (27%) medium and 27 (10%) had high cyclin E content. Fifty-six percent (15/27) of the breast cancers with high cyclin E had p53 gene mutations, compared with 14% (24/171) of those with low cyclin E content (p<0.0001). In p53 mutated breast cancers high cyclin E content was associated with insertions, deletions and nonsense point mutations in the p53 tumor suppressor gene, whereas low cyclin E was linked to p53 missense point mutations. We also observed statistically significant associations between a high cyclin E content and aneuploidy, high S-phase, larger tumor size, estrogen receptor negativity, presence of axillary node metastases and high tumor grade. High cyclin E content was associated with poor overall survival in univariate and multivariate analysis (Hazard ratio 2.4, 95% Confidence limits: 1.3-4.5). In summary, our findings demonstrate that overexpression of cyclin E is associated with an aggressive tumor phenotype and specific types of p53 mutations.
Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer
2 Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden
3 Department of Oncology, Uppsala University - Gävle County Hospital, Gävle, Sweden
4 Department of Pathology, Uppsala University Hospital, Uppsala, Sweden
5 Uppsala-Örebro Regional Oncologic Center, Uppsala, Sweden
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