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 lowerrisk of metastasis and death in operable patients

Apoptosis is an important physiological process controlled by multiple gene s, including c-myc, 53 and bcl-2, and its inhibition may lead to the develo pment 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 immunohistoch emistry in 175 breast tumor specimens obtained from patients with operable breast cancer. We evaluated the relation between expression of these 3 gene s and (i) the main usual prognostic factors (tumor size, histo-prognostic g rade, hormone receptors and number of positive nodes); (ii) the risk of dea th 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-expressio n 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) a nd hormone receptor-negative (p = 0.0001) tumors. In contrast, bcl-2 protei n 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 we re independently linked to the risk of death: number of positive nodes, whi ch increased the risk (p = 0.0001), and bcl-2 protein overexpression, which decreased the risk(p = 0.008). When bcl-2 over expression was studied in r elation to nodal status, hormone receptor status and chemo- and hormone the rapy, 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 char acterizes a particular phenotype of breast cancer with a favorable prognosi s, and it may therefore be used as a marker of long-term survival, Int. J. Cancer (Pred. Oncol.) 84:562-567, 1999. (C) 1999 Wiley-Liss, Inc.