p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer

Abstract

SummaryThe role and prognostic value of the tumour suppressor p21/WAF1 expression in epithelial ovarian cancer has not yet been defined. Therefore, the expression of p21/WAF1 was assessed immunohistochemically (IHC) in 316 epithelial ovarian malignancies in relation to p53, cell proliferation and patient survival. p21/WAF1 expression was inversely correlated with p53 and cell proliferation. Low p21/WAF1 expression was significantly associated with high grade of the tumour (P = 0.0005), advanced FIGO stage (P = 0.001) and primary residual tumour (P = 0.0001). Low p21/WAF1 expression was a marker of poor overall survival (P = 0.012). Similarly, p53-positivity and high cell proliferative activity were significant predictors of poor survival in univariate analyses. Moreover, the patients with p21-/p53+ tumours had a poorer overall (P < 0.00005) and recurrence-free (P = 0.0005) survival in univariate analyses, and the p21/p53 expression independently predicted tumour recurrence in Cox's multivariate analysis. Our results suggest that p21/WAF1 expression is mostly p53-dependent in epithelial ovarian cancer. High p21/WAF1 expression seems to function as a negative cell cycle regulator and as a marker of favourable disease outcome in epithelial ovarian cancer. In addition, the patients with their tumour expressing no or low p21/WAF1 protein but positive for p53 had a notably higher risk of recurrent disease, implicating that these patients might be more prone to treatment failures.

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2

“…This is consistent with findings from several other studies (Baekelandt et al, 1999a(Baekelandt et al, , 1999bDiebold et al, 1996;Herod et al, 1996;Marone et al, 1998) although an inverse correlation between TP53 and BCL-2 (Henriksen et al, 1995) and between TP53 and p21 (Anttila et al, 1999) has also been reported in ovarian tumour tissues. The lack of a correlation between TP53 and its downstream genes may reflect the fact that expression of these genes is also regulated by TP53-independent pathways.…”

“…This is in agreement with a recent report that also failed to find an association between p21 expression and prognosis or response to platinum-based chemotherapy in specimens from stage III ovarian cancer patients (Baekelandt et al, 1999a). In contrast to these findings Anttila et al (1999) reported that low p21 expression, using a polyclonal antibody, is a marker of poor overall survival.…”

Microarray analysis of gene expression mirrors the biology of an ovarian cancer model

“…Some of the examples in Table 3 illustrate the concordance in microarray analysis with previous published reports based on Northern blot analysis and immunohistochemistry. In particular, both CDKN1A (Anttila et al, 1999) and SPARC (Mok et al, 1996) have been shown to be down-regulated in aggressive ovarian cancer and this mirrors the situation revealed by microarray expression analysis in our model. Once again, for these genes the pattern of expression of NOV-31 and TOV-81D are highly similar, and contrast sharply with the aggressive EOC samples.…”

“…It is possible to compare the expression pattern of genes previously described in ovarian cancer (Anttila et al, 1999;Asschert et al, 1997;Barboule et al, 1998;Brown et al, 1999;Chambers et al, 1998;Courjal et al, 1996;Huleihel et al, 1997;Mok et al, 1996;Neyns et al, 1996;Tanner et al, 1998;Wysocki et al, 1990) with the expression values generated by microarray analysis. Some of the examples in Table 3 illustrate the concordance in microarray analysis with previous published reports based on Northern blot analysis and immunohistochemistry.…”

p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis

“…Elsewhere p21 induction has been observed to be p53-independent in breast cancer (Rey et al, 1998), ovarian cancer (Elbendary et al, 1996;Anttila et al, 1999) and in human leukaemia . Our results suggested a p53-independent mechanism of p21 activation only in a subgroup of patients (Table 3).…”