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

Although the link between the BRCA1 tumour-suppressor gene and hereditary b reast and ovarian cancer is established(1-5), the role, if any, of BRCA1 in non-familial cancers is unclear. BRCA1 mutations are rare in sporadic canc ers(6-8), but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization(9,10) is postulated to be important in non-familia l breast and ovarian cancers. Epigenetic loss, however, has not received ge neral acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear(11 -15), to conditionally nuclear(10), to the ER/golgi(16), to cytoplasmic inv aginations into the nucleus(17). In an attempt to resolve this issue, we ha ve comprehensively characterized 19 anti-BRCA1. antibodies. These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelia l cell lines, including those derived from breast malignancies. Immunohisto chemical staining of human breast specimens also revealed BRCA1 nuclear foc i in benign breast, invasive lobular cancers and low-grade ductal carcinoma s. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may con tribute to the pathogenesis of a significant percentage of sporadic breast cancers.