APOPTOSIS LOSS AND BCL-2 EXPRESSION - KEY DETERMINANTS OF LYMPH-NODE METASTASES IN T-1 BREAST-CANCER

The Bcl-2 proto-oncogene extends cell survival but does not confer any proliferative advantage to cells that express it. Thus, the loss of a poptosis may have a role in progression allowing the acquisition of ad ditional mutations, To determine whether apoptosis loss at diagnosis i s associated with the metastatic advantage of ductal breast carcinomas and to examine the relationship between Bcl-2 expression, p53, and tu mor cell death status, we examined tumor samples from 116 patients dia gnosed with T-1 (2 cm or less) breast cancer with (n = 49) or without (n = 67) lymph node metastases, Apoptosis loss in histological section s was considered when <1% of tumor nuclei were stained with terminal d eoxynucleotidyl transferase labeled with biotin, We studied the expres sion of Bcl-2 and p53 by immunohistochemistry and in 37 p53 mutations by single-strand conformational polymorphism analysis and cycle sequen cing, Multivariate logistic regression modeling was used to estimate p revalence odds ratios (pORs) for apoptosis loss and presence of lymph node metastases, Patients with marked apoptosis loss in their tumor ce lls were about 5 times more likely to present lymph node metastases th an those with no apoptosis loss in their tumor cells (adjusted pOR, 4. 7; 95% confidence interval, 1.4-15.6; trend test, P = 0.008), Bcl-2 ex pression was strongly associated with both apoptosis loss (pOR, 6.9; t rend test, P < 0.0001) and presence of lymph node metastases (pOR, 5.7 ; trend test, P = 0.002), These associations were more evident in hist ological grade I and II tumors than in poorly differentiated histologi cal grade III tumors and in p53-negative tumors than in p53-positive t umors, This study demonstrates for the first time that the lymphatic p rogression of T-1 human breast cancer is strongly related to apoptosis loss.