Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype.

Recent studies have suggested that BRCA1-associated hereditary breast cancer may be a more aggressive form of disease than sporadic breast cancer. BRCA1-associated breast cancer has been reported to be significantly associated with grade 3 disease. Because grade 3 disease indicates a poor prognosis, this implies that women with a germ-line mutation in BRCA1 who develop breast cancer may have a poorer prognosis than those with sporadic disease. However, little is known about the association of BRCA1 expression with biological markers of prognosis. The present study examined the expression of BRCA1 in a total of 40 archival breast tumor specimens from three patient cohorts (sporadic, familial, and early onset breast cancer) to determine localization of the protein. Furthermore, BRCA1 staining was compared with expression of markers of tumor biology. We found that BRCA1 is generally located in the nucleus and the cytoplasm of normal and malignant breast tissue. Nuclear staining for BRCA1 was observed in most sporadic tumors, but nuclear BRCA1 was reduced or absent in the majority of familial and early onset breast tumors. Although no correlation was found between nuclear BRCA1 expression and estrogen and progesterone status, a significant inverse correlation was found between nuclear BRCA1 and expression of the proliferation marker Ki-67 (P = 0.01). Our findings suggest that tumors associated with a germ-line mutation in one of the breast cancer genes may be highly proliferative and support the view that loss of BRCA1 expression in breast tumors may lead to a more aggressive tumor phenotype.