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Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3 and E) are crucial for cell cycle progression [1]. Secondary cyclins (C and H) have putative indirect effects on cell cycle propulsion and have not been previously evaluated in breast cancer. We have examined protein expression and gene amplification of cyclins in breast carcinomas and correlated the findings with clinical follow-up data. We have previously demonstrated that overexpression of cyclin A is associated with poor prognosis in breast cancer patients [2]. In this study we wanted to evaluate the impact of other cyclins, both at the gene level and at the protein level. We wanted to evaluate whether the overexpression of cyclins is a result of gene amplification, as well as to evaluate the prognostic value of gene amplification of different cyclins for breast cancer patients. The impact of TP53 gene mutations on gene amplification of cyclins was also evaluated.  Real-time quantitative PCR was used to detect gene amplification of cyclin A, cyclin B1, cyclin C, cyclin D1, cyclin D3, cyclin E and cyclin H in tumour tissue from 80 patients operated for invasive breast carcinomas, while immunohistochemistry was applied to detect protein expression of the same cyclins.  Among the 80 breast cancer tumour samples examined, 26.7% was defined to have ccnA2 gene amplification, 37.2% had ccnB1 gene amplification, 82.6% of the samples harboured amplification of ccnC, 74.4% had ccnD1 gene amplification, 41.9% had ccnD3 gene amplification, 29.1% of the patients had ccnE gene amplification and 9.3% of the samples showed amplification of the ccnH gene.  When correlation between gene amplification and protein expression was evaluated, we observed a statistical significant correlation between gene amplification and protein expression of cyclin A (correlation coefficient = 0.287, P = 0.009) and cyclin D3 (correlation coefficient = 0.906, P = 4.9 × 10-33). Protein expression as well as gene amplification of cyclin A was also correlated with gene amplification of other cyclins. When the impact of gene amplification of different cyclins on the patient survival was analysed, only gene amplification of cyclin A was associated with patient survival.  We found a significant interaction between amplification of cyclin A and cyclin E (Cox regression, P = 0.02). These two cyclins are sequentially time related in the cell cycle. The effect of amplification of cyclin A was therefore tested in a stratified analysis both when the cyclin E gene was not amplified and when the cyclin E gene was amplified. When the cyclin E gene was not amplified, the statistical strength of the cyclin A amplification increased with a HR of 5.5 (95% confidence interval: 2.2–14.3, P < 0.0001). When cyclin E was amplified, amplification of cyclin A had no significant impact on survival (P = 0.45).  In summary, we have analysed gene amplification and protein expression of both primary and secondary cyclins in invasive breast carcinomas. Overexpression and gene amplification of cyclin A is correlated with gene amplification of other cyclins. Only gene amplification and overexpression of cyclin A was associated with poor prognosis, and amplification of cyclin A is the strongest prognostic factor in patients that have a normal amplicon of cyclin E.

breast cancer research

Protein expression and gene amplification of primary cyclins (A, B1, D1, D3and E) and secondary cyclins (C and H) in relation to prognosis in breast cancer patients