Low expression of bcl-2 in Brca1-associated breast cancers

tittle data are available concerning the molecular mechanisms of action of Brca1 and Brca2 in breast oncogenesis. Recent experimental results suggest that Brca1 plays a role in the regulation of apoptosis. In order to determi ne whether the analysis of human tumours would provide data supporting this hypothesis, we have assessed the expression of the antiapoptotic bcl-2 and of the proapoptotic p53 genes in Brca1- and Brca2-associated breast carcin omas. The levels of expression of these genes were compared to those observ ed in controls and to the mitotic and the apoptotic indexes. Our series wer e composed of 16 cases of breast carcinoma in women with a germline Brca1 g ene mutation, and of four cases with Brca2 mutation. A group of 39 patients aged under 36 years and for whom the search for Brca1 gene mutations was n egative, and a group of 36 cases of sporadic cancers without data on their Brca status were used as controls. Immunohistochemistry was used to detect p53 and bcl-2 gene products. Mitotic and apoptotic indexes were higher in B rca1-associated tumours than in controls. No significant difference in p53 immunostaining was observed between the four groups of patients. In contras t, the rate of bcl-2-positive tumours was lower (31%) in Brca1-carcinomas t han in carcinomas without Brca 1 mutation (90%) (P < 10(-3)). A strong Bcl- 2 expression was found in the lour cases of Brca2-associated carcinomas. No significant correlation was observed between p53 and Bci2 immunostainings, either in cases or in controls. The association between Brca1 status and B cl-2 expression remained significant after adjustment for the oestrogen rec eptor status. Our study shows that a low expression of bcl-2 characterises most Brca1-associated breast carcinomas, a biological trait which seems not to be shared by Brca2-associated tumours nor to be related to oestrogen re ceptor and/or p53 status. bcl-2 might thus be one of the target genes invol ved in the oncogenesis related to Brca I and its down-regulation may accoun t for the increased apoptosis and the high proliferative rate observed in B rca I-associated carcinomas. (C) 2000 Cancer Research Campaign.