p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis.
OBJECTIVE
To evaluate the expression and prognostic relevance of p21(WAF1) in breast cancer and to investigate its association with p53, activator protein 2 (AP-2), and cell proliferation (as assessed by Ki-67 expression).


METHODS
p21(WAF1) expression was analysed immunohistochemically in a large prospective, consecutive series of 420 patients with breast cancer diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. Inter-relations between p21(WAF1) expression and p53, AP-2, and Ki-67 were evaluated. The expression of p21(WAF1) was also compared with clinicopathological parameters and the patients' survival.


RESULTS
In general, nuclear p21(WAF1) expression was low in carcinomas (median, 2.5%; range, 0-70%). Expression was lowest in lobular carcinomas (chi(2) = 7.4; p = 0.025). p21(WAF1) positive tumours were more often p53 positive (chi(2) = 4.2; p = 0.041) but expression of p21(WAF1) did not correlate with AP-2 expression or Ki-67 in the whole patient group. In addition, the combined expression of p21 and p53 was not associated with AP-2 expression. High nuclear p21(WAF1) positivity (n = 160; 38%) was associated with poor differentiation (chi(2) = 8.1; p = 0.017). In the univariate analyses, p21(WAF1) expression had no prognostic value for predicting breast cancer related survival (BCRS) or recurrence free survival (RFS) in the whole patient group or in the subgroups investigated. However, in postmenopausal patients with lymph node metastases, and oestrogen receptor (ER) and/or progesterone receptor (PR) positive tumours, high p21(WAF1) expression predicted response to adjuvant hormonal treatment with antioestrogens. In the univariate analysis, the significant factors for predicting BCRS were Ki-67 expression, stage, lymph node status, histological grade, ER and PR status, and those for RFS were Ki-67 expression, stage, and lymph node status. In the multivariate analysis, the independent predictors of shorter BCRS were high cell proliferation activity measured by Ki-67 expression (p < 0.001), advanced stage (p < 0.001), and poor differentiation (p = 0.048). Shorter RFS was independently predicted by high cell proliferative activity (p < 0.001) and advanced stage (p < 0.001).


CONCLUSIONS
The regulation of p21(WAF1) seems to occur independently of p53 or AP-2 and analysing p21(WAF1) expression provided no prognostic information for patients with breast cancer.
Pellikainen
M J
MJ
Department of Pathology and Forensic Medicine, University of Kuopio, FIN-70211 Kuopio, Finland.
Pekola
T T
TT
Ropponen
K M
KM
Kataja
V V
VV
Kellokoski
J K
JK
Eskelinen
M J
MJ
Kosma
V-M
VM
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D033962:Adaptor Protein Complex 2; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53