OVEREXPRESSION OF BCL-X PROTEIN IN PRIMARY BREAST-CANCER IS ASSOCIATED WITH HIGH TUMOR GRADE AND NODAL METASTASES

PURPOSE Dysregulation of genes that control apoptosis can contribute t o tumor progression and increased drug resistance. The BCL2 gene and i ts family member BCL-x as well as the TP53 genes regulate apoptosis an d have been shown to have a direct effect on the sensitivity of cancer cells to radiation and chemotherapeutic agents. METHODS The expressio n of BCL-x, a BCL2-related protein that is a potent inhibitor of apopt osis, was investigated by immunohistochemical and immunoblot methods i n 43 primary unheated breast carcinomas, in conjunction with BCL2 and TP53. RESULTS BCL-x protein was overexpressed in 18 of 42 (43%) invasi ve breast cancers when compared with adjacent normal breast epithelium . Western blot analysis of eight primary breast cancers and five breas t cancer cell lines indicated that BCL-x(L) was the predominant BCL-x protein expressed. Overexpression of BCL-x protein in these tumors was associated with higher turner grade and increased number of positive nodes. In contrast, BCL2 protein was overexpressed in 19 of 42 tumors (45%) and was strongly correlated with astrogen receptor positivity, l ower tumor grade, smaller tumor size, and lower stage. TP53 protein im munostaining was detected in 12 of 40 tumors (29%) and was inversely c orrelated with BCL2 expression and ER positivity. There was no correla tion between the level of BCL-x protein expression and age, tumor size , ER status, and TP53 status. At a median follow-up time of 216 weeks, there was a trend toward decreased overall survival in patients with tumors overexpressing BCL-x. CONCLUSIONS These findings suggest that e xpression of BCL-x protein is increased in a significant fraction of i nvasive breast cancers. In contrast to BCL2 expression, up-regulation of BCL-x protein may be a marker of tumor progression. Additional data including larger numbers of patients, more uniform treatments, and lo nger follow-up are needed to define the prognostic significance overex pression of BCL-x during breast cancer progression.