Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian cancer syndrome, To clarify the possible involvement of the BRC A1 protein in mammary carcinogenesis in sporadic and hereditary forms, we h ave analyzed the BRCA1 protein expression pattern in five breast epithelial cell lines, including a BRCA1-deficient cell line, and 162 breast cancer t issue samples [including 108 sporadic, 35 hereditary (BRCA1 status unknown) , and 19 BRCA1-associated cases] from Japanese women. Twelve anti-BRCA1 ant ibodies were tested by fixation conditions, in which nuclear localization o f BRCA1 protein was preserved, and by specificity of the antibodies, which was evaluated in BRCA1-deficient cancer cells. Using monoclonal antibodies applicable to immunohistochemical analysis of paraffin-embedded tissue sect ions, we found high-level expression of BRCA1 protein in normal mammary epi thelium and various degrees of reduced expression in breast cancer cells. O f the 19 BRCA1-associated breast cancer tissues, 15 (79%) showed reduction (8 cases) or complete loss (7 cases) of nuclear expression. Thirty (28%) of 108 sporadic and 6 (17%) of 35 hereditary carcinomas showed reduced BRCA1 protein expression. Reduction of BRCA1 protein expression in sporadic carci nomas was associated with solid-tubular phenotype, with poor tubular differ entiation, and with an overexpression of c-erbB-2 protein, which is one of the prognostic factors in breast cancer. Our data suggest that reduced expr ession of BRCA1 protein may play an important role in mammary carcinogenesi s, not only in BRCA1-associated breast carcinomas, but also in sporadic car cinomas, and also suggest that mechanisms other than mutation may be involv ed in its reduced expression.