The cell cycle occupies a pivotal role in the control of cellular proliferation, a critical point being activation of CyclinE which is held in check by the inhibitor p27. CyclinE is targeted for degradation by the F-box protein Archipelago (Ago/Fbw7/cdc4), while p27 is exported out of the nucleus by Jun activation domain-binding protein 1 (Jab1). Over-expression of CyclinE has been reported in breast cancer. We have now explored the role of Jab1 and Ago in mediating changes in CyclinE in breast cancer.
We obtained Local Ethical Committee approval for all studies. We evaluated the mRNA expression levels of CyclinE, Ago and Jab1 in 38 malignant breast cancers and their 'adjacent normal' tissue and 5 normal breast tissue samples using real-time quantitative PCR. CyclinE expression was increased in tumour (P<0.001) compared to 'adjacent normal' (P<0.001) and normal breast tissue (P=0.015). Ago expression was increased in 'adjacent normal' (P=0.017) compared to both tumour (P=0.027) and normal (P=0.017). Jab1 expression was increased in tumour compared to both 'adjacent normal' (P=0.05) and normal breast tissue (P<0.001). Importantly, Jab1 expression in 'adjacent normal' was significantly increased compared to normal breast tissue (P=0.003).
We have therefore confirmed the over-expression of CyclinE mRNA in breast cancer previously reported. However, the graded increase in expression of Jab1 from normal tissue to 'adjacent normal' to tumour indicates that Jab1 may be responsible for excluding p27 from the nucleus, allowing CyclinE protein to accumulate, and may thus indicate instability of even the apparently normal tissue surrounding the tumour. The increased expression of Ago in this 'adjacent normal' may be responsible for counteracting this change in CyclinE protein expression. The protein correlates of these mRNA changes are under further study.
04 - 06 Apr 2005
British Endocrine Societies