THE EXTENT OF PROLIFERATIVE AND APOPTOTIC ACTIVITY IN INTRADUCTAL ANDINVASIVE DUCTAL BREAST CARCINOMAS DETECTED BY KI-67 LABELING AND TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-11-DUTP NICK END LABELING

BACKGROUND. The balance among cell proliferation, cell differentiation , and cell death determines the cell number in a population as well as the size or even the stage of a tumor. Thus, to improve our understan ding of the pathogenesis of neoplasms, it is important to investigate the regulation of both cell proliferation and cell death. METHODS. Thi s study examined the occurrence of apoptosis and proliferative capacit y in 46 breast carcinomas: 20 intraductal carcinomas (ductal carcinoma s in situ [DCIS]) and 26 infiltrative ductal carcinomas (IDC). Termina l deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end l abeling (TUNEL) and immunostaining with the Ki-67 antibody were used i n the examination. A ladder of DNA fragments induced by apoptosis was demonstrated by means of DNA agarose gel electrophoresis in 10 of the available TUNEL positive and negative samples. RESULTS. The results we re correlated with p53, bcl-2, estrogen receptor (ER), and progesteron e receptor (PR) protein expression, which would suggest association wi th apoptosis by immunohistochemistry. The apoptosis and proliferation of each cancer were expressed as the number of tumor cells undergoing apoptosis and proliferation per 1000 tumor cells. The extent of apopto sis was more frequently observed in DCIS than in LDC (21.9 +/- 6.8 vs. 4.0 +/- 0.9, P < 0.001), and the proliferation activity was significa ntly higher in IDC than in DCIS (16.8 +/- 6.5 vs. 3.5 +/- 0.8, P < 0.0 06). Apoptosis associated with MIB-1 positive cells and TUNEL labeling was significantly higher in IDC than in DCIS (3.26 vs. 0.42, P = 0.00 1). In DCIS, apoptosis was correlated with p53 (r = 0.663, P = 0.005), and p53 had a reverse correlation with bcl-2 (r = 0.620, P = 0.018). Moreover, bcl-2 expression was associated with ER (P = 0.028) and PR ( P = 0.005) expression in both DCIS and IDC. CONCLUSIONS. The results o f this study show that a higher degree of apoptosis and lower prolifer ation activity in intraductal carcinoma result in a steady-state, self -renewing condition in which net growth of the tumor is rare. The resu lts also indicate that apoptosis was altered by the expression of p53, bcl-2, ER, and PR. (C) 1998 American Cancer Society.