Subcellular localisation of cyclin B, Cdc2 and p21(WAF1/CIP1) in breast cancer. association with prognosis.

The heterodimeric cyclin B/Cdc2 protein kinase governs entry into mitosis, and can be negatively regulated through p53-mediated transcriptional induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). Ectopic expression of p21(WAF1/CIP1) in cultured cells has been shown previously to influence the subcellular distribution of the cyclin-dependent kinases (CDKs) including Cdc2. In this study, we have examined the subcellular localisation of Cdc2, cyclin B and p21(WAF1/CIP1) by immunohistochemistry in a well characterised series of primary breast cancers. Surprisingly, p21(WAF1/CIP1) was predominantly cytoplasmic in many of the tumours, where it was associated with high p53 levels; cytoplasmic p21(WAF1/CIP1) and high cyclin B levels were also significant predictors of poor prognosis. We conclude that breast tumorigenesis may be characterised by abnormalities in pathways determining not only levels of expression of key regulatory molecules, but also their subcellular localisation. Investigation of the subcellular distribution of cell cycle regulatory proteins, particularly p21(WAF1/CIP1), could provide valuable prognostic markers in breast cancer.