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.
Winters
Z E
ZE
Imperial Cancer Research Fund Molecular Oncology Laboratory, University of Oxford Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Hunt
N C
NC
Bradburn
M J
MJ
Royds
J A
JA
Turley
H
H
Harris
A L
AL
Norbury
C J
CJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000737:chemistry*; D016203:CDC2 Protein Kinase / Q000032:analysis*; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry*; D019926:Cyclin B / Q000032:analysis*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis*; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000032:analysis*; D009364:Neoplasm Recurrence, Local / Q000737:chemistry; D011237:Predictive Value of Tests; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
C493956:CDKN1A protein, human; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase