Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: Apathway to metastatic progression in human breast cancer

We have examined whether the extended life span of cells induced by Bcl-2 i n T-1 ductal breast carcinomas might favor the acquisition and accumulation of genetic alterations that induce lymph node metastases, We analyzed the expression of c-Myc, c-erbB-2 and epidermal growth factor receptor by immun o-histochemistry in a group of 142 T-1 (<2 cm) ductal breast carcinomas emb edded in paraffin, previously studied for p53 mutation and Bcl-2 over-expre ssion. We also measured the apoptotic status and estimated the excess risk (pOR) for lymph node metastasis according to the number of accumulated onco gene alterations and Bcl-2 and p53 expression, The linear relationship betw een number of oncogene alterations and presence of lymph node metastasis wa s statistically significant in Bcl-2-positive tumors (trend test, p = 0.03) , p53-mutated tumors (trend test, p = 0.08) and tumors with loss of apoptos is (trend test, p = 0.08). Very large associations (pOR > 12) between the n umber of oncogene alterations and lymph node metastasis were observed among Bcl-2-positive tumors that showed increased loss of apoptosis (trend test, p = 0.03). Furthermore, in p53-negative tumors, a strong linear associatio n was found between the number of oncogene alterations and risk of lymph no de metastasis among Bcl-2-positive tumors (trend test, p = 0.03). In human T-1 ductal breast carcinoma, over-expression of Bcl-2 along with loss of ap optosis might render breast cancer cells susceptible to the acquisition of additional genetic lesions related to disease progression among p53-negativ e tumors. Thus, in breast cancer, there are at least 2 pathways to progress ion: Bcl-2- and p53-dependent mechanisms. (C) 2000 Wiley-Liss, Inc.