p21(waf) correlates with DNA replication but not with prognosis in invasive breast cancer.
OBJECTIVE
p21(waf) plays a central role both in the regulation of the cell cycle and in DNA replication. Accordingly, p21(waf) is a putative tumour suppressor. The role of p21(waf) expression in breast cancer is still unclear, particularly with respect to the clinical situation. Therefore, this retrospective study was designed to investigate the value of immunohistochemically detected p21(waf) expression in invasive breast cancer.


METHODS
Cellular expression of p21(waf) was assessed in 307 breast cancer tissues by immunohistochemistry using the monoclonal antibody, clone 4D10. The data were correlated to established and functional factors of prognosis (age, menopausal status, tumour size, nodal status, tumour grade, receptor status, proliferating cell nuclear antigen (PCNA) expression, Her-2/neu expression, and p53 expression), and to clinical follow up (median observation time, 82 months).


RESULTS
Ninety nine of 307 (32.2%) tumour tissues were considered p21(waf) positive (nuclear staining). In the entire study group, p21(waf) expression correlated only with increased PCNA expression (chi(2) test: p = 0.029), and with none of the other investigated markers. In node negative patients (n = 134), p21(waf) expression correlated with increased tumour size and increased PCNA expression, whereas the node positive subgroup (n = 161) showed no correlation with these parameters (lymphonodectomy was done in 295 women). With respect to clinical outcome, p21(waf) expression showed a definite favourable trend in both subgroups (N0: p21(waf) negative, 23 of 87; p21(waf) positive, nine of 43. N+: p21(waf) negative, 63 of 107; p21(waf) positive, 23 of 52), but this observation was not significant (p > 0.05). Multivariate analysis for disease free survival as indicated by Cox regression analysis included all factors investigated. The most striking parameters were nodal status (relative risk (RR), 1.74; p = 0.00001), receptor status (RR, 0.59; p = 0.0085), tumour size (RR, 1.42; p = 0.02), and Her2/neu expression (RR, 1.56; p = 0.033). p21(waf) expression was not significant in the multivariate analysis (p > 0.05).


CONCLUSIONS
p21(waf) expression is an independent factor but fails to be of prognostic or predictive value in multivariate analysis. These data confirm the hypothesis of a p53 independent p21(waf) induction and suggest a functional role in the inhibition of PCNA mediated DNA replication.
Göhring
U J
UJ
Department of Gynecology and Obstetrics, University of Cologne, 50924 Cologne, Germany.
Bersch
A
A
Becker
M
M
Neuhaus
W
W
Schöndorf
T
T
D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis*; D004261:DNA Replication; D018572:Disease-Free Survival; D029721:Drosophila Proteins; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008025:Ligases; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D044767:Ubiquitin-Protein Ligases
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D029721:Drosophila Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C071006:neur protein, Drosophila; D008025:Ligases