MIB‐1 Proliferation Index in Ductal Carcinoma In Situ of the Breast: Relationship to the Expression of the Apoptosis‐Regulating Proteins bcl‐2 and p53

Abstract

Tumor growth is the net result of cell proliferation and cell death. To investigate the relationship between these phenomena in ductal carcinoma in situ (DCIS), we studied proliferation index (PI) in DCIS in relation to the expression of two proteins involved in the regulation of cell death, bcl-2 and p53. Thirty-nine consecutive cases of DCIS were studied. PI was determined using immunolabeling with the monoclonal antibody MIB-1. The proportion of MIB-1-positive nuclei among 500 tumor cell nuclei was determined for each case and constituted the PI. All cases were also assessed immunohistochemically for bcl-2 and p53 protein expression. DCIS cases were graded using the criteria of Holland et al. PI ranged from 0 to 57% (mean 11.2%, median 4.6%). PI was significantly lower in well-differentiated and intermediately differentiated DCIS cases (mean 7.3% and 4.8%, respectively) than in poorly differentiated lesions (mean 24%, p = 0.01). PI was significantly lower in bcl-2-positive cases than in bcl-2-negative cases (mean PI for bcl-2-positive cases 6% and for bcl-2-negative cases 26%, p = 0.01). PI was higher in lesions expressing the p53 protein than in p53 negative cases (19% versus 8.3%), but this difference did not reach statistical significance. PI was also examined in relation to combinations of bcl-2 and p53 expression. Twenty-five of the DCIS lesions (64%) showed the bcl-2-positive/p53-negative phenotype which is similar to that seen in normal breast tissue and benign lesions and can be considered the “physiologic” combination. Among these cases the mean PI was 6.4%. In contrast, 14 cases showed “aberrant” combinations of bcl-2 and p53 expression suggesting dysregulated control of apoptosis. Among these cases the mean PI was 19.6% (p = 0.03). The highest mean PI was in cases with the bcl-2-negative/p53-positive phenotype (PI = 29.7%). DCIS lesions with the physiologic bcl-2-positive/p53-negative phenotype have low PI. In contrast, DCIS lesions with “aberrant” bcl-2/p53 phenotypes have high PI. This combination may favor tumor growth and progression in DCIS.