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p21^WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis

¹ Department of Pathology and Forensic Medicine, University of Kuopio, FIN-70211 Kuopio, Finland
² Department of Pathology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland
³ Department of Oncology, Kuopio University Hospital
⁴ Department of Surgery, Kuopio University Hospital
⁵ Department of Otorhinolaryngology, Oral and Maxillofacial Unit, Kuopio University Hospital
⁶ Department of Pathology, Centre for Laboratory Medicine, Tampere University Hospital, FIN-33521 Tempere, Finland

Correspondence to:
Dr V-M Kosma, Department of Pathology, Centre for Laboratory Medicine, Tampere University Hospital, PO Box 2000, FIN-33521, Tampere, Finland;
VeliMatti.Kosma{at}ta.fi Aims: 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 (² = 7.4; p = 0.025). p21^WAF1 positive tumours were more often p53 positive (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 (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.

Keywords: p21^WAF1; breast cancer; prognosis; prospective

Abbreviations: ABC, avidin; biotin; peroxidase complex; AP-2, activator protein 2; BCRS, breast cancer related survival; CDK, cyclin dependent kinase; ER, oestrogen receptor; IHC, immunohistochemistry; PBS, phosphate buffered saline; pN+, node positive; pN-, node negative; PR, progesterone receptor; pRb, retinoblastoma protein; RFS, recurrence free survival

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