Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas

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Abstract
Although the link between the BRCA1 tumour–suppressor gene and hereditary breast and ovarian cancer is established1,2,3,4,5, the role, if any, of BRCA1 in non–familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers6,7,8, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization9,10 is postulated to be important in non–familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear11,12,13,14,15, to conditionally nuclear10, to the ER/golgi16, to cytoplasmic invaginations into the nucleus17. In an attempt to resolve this issue, we have comprehensively characterized 19 anti–BRCA1 antibodies. These reagents detect a 220–kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low–grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high–grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.