Overexpression of clusterin in human breast carcinoma

Clusterin has been implicated in numerous processes including active cell d eath, immune regulation, cell adhesion and morphological transformation. Th e purpose of this study was to examine clusterin expression in a large seri es of breast carcinomas by immunohistochemistry and in situ hybridization, The study included 40 samples of non-neoplastic glandular epithelia, 42 ben ign lesions, 15 atypical intraductal hyperplasias, 35 carcinomas in situ, 1 14 invasive carcinomas, and lymph node metastases from 40 patients. Epithel ial normal cells were always negative for clusterin expression and only 19% of the benign lesions presented positive staining, In contrast to the beni gn lesions, however, the frequency of clusterin positive samples increased in atypical hyperplasias (47%, P = 0.08), intraductal carcinomas (49%, P = 0.01) and invasive carcinomas (53%, P < 0.001). Positive staining presented a cytoplasmic pattern, except in 3 cases of invasive carcinomas which had nuclear staining. Clusterin mRNA by in situ hybridization confirmed the spe cific cellular pattern of clusterin expression by immunohistochemistry. Clu sterin expression was associated with large tumor size (P = 0.04), estrogen and progesterone receptor negative status (P = 0.02 and P = 0.001, respect ively) and with the progression from primary carcinoma to metastatic carcin oma in lymph nodes (80% metastatic nodes had positive expression) (P = 0.00 4). Ten of 15 (67%) primary carcinomas without clusterin expression became positive in lymph node metastases, while most (22 of 25, 88%) of the cluste rin-positive primary carcinomas were also immunoreactive in metastases. In survival analysis, clusterin expression did not represent a prognostic indi cator by uni- or multivariate analysis. The increased clusterin expression in breast carcinomas tended to correlate inversely with the apoptotic index (P = 0.09) which Indicates that clusterin gene expression is not a prerequ isite to cellular death by apoptosis. From these results, we suggest that c lusterin may have a role in tumorigenesis and progression of human breast c arcinomas.