c‐myc, p53 and bcl‐2, apoptosis‐related genes in infiltrating breast carcinomas: Evidence of a link between bcl‐2 protein over‐expression and a lower risk of metastasis and death in operable patients

Apoptosis is an important physiological process controlled by multiple genes, including c‐myc, p53 and bcl‐2, and its inhibition may lead to the development of human cancers. In this study, we analyzed expression of the c‐myc gene using Northern blot and of the p53 and bcl‐2 proteins by immuno‐histochemistry in 175 breast tumor specimens obtained from patients with operable breast cancer. We evaluated the relation between expression of these 3 genes and (i) the main usual prognostic factors (tumor size, histo‐prognostic grade, hormone receptors and number of positive nodes); (ii) the risk of death and relapse, taking into account these 4 factors, after a mean period of follow‐up of 9.5 years (SD 2 years). Over‐expression of c‐myc, p53 and bcl‐2 was observed in 35%, 23% and 63% of tumors, respectively. Over‐expression of c‐myc was strongly linked to the number of positive nodes (p = 0.0005). p53 protein expression was associated with both high‐grade (p = 0.0001) and hormone receptor‐negative (p = 0.0001) tumors. In contrast, bcl‐2 protein over‐expression was associated with the main favorable prognostic factors and, more particularly, with hormone receptor‐positive tumors (p = 0.0001). Multivariate analysis, using the Cox model, showed that only 2 factors were independently linked to the risk of death: number of positive nodes, which increased the risk (p = 0.0001), and bcl‐2 protein over‐expression, which decreased the risk (p = 0.008). When bcl‐2 over‐expression was studied in relation to nodal status, hormone receptor status and chemo‐ and hormone therapy, no significant difference was observed between different subgroups of patients. bcl‐2 expression was also associated with a significantly lower risk of distant metastasis (p = 0.04). In conclusion, bcl‐2 expression characterizes a particular phenotype of breast cancer with a favorable prognosis, and it may therefore be used as a marker of long‐term survival. Int. J. Cancer (Pred. Oncol.) 84:562–567, 1999. © 1999 Wiley‐Liss, Inc.