BRCA1-associated growth arrest is RB-dependent

BRCA1 is a susceptibility gene for breast and ovarian cancer with growth-in hibitory activity for which the mechanism of action remains unclear, When i ntroduced into cells, BRCA1 inhibits growth of some but not all cell lines. In an attempt to uncover the mechanism of growth suppression by BRCA1, we examined a panel of cell lines for their ability to reduce colony outgrowth in response to BRCA1 overexpression. Of all variables tested, only those c ells with wild-type pRb were sensitive to BRCA1-induced growth suppression. In cells with an intact rb gene, inactivation of pRb by HPV E7 abrogates t he growth arrest imposed by BRCA1. In accordance with these observations, w e found that BRCA1 could not suppress BrdUrd uptake in primary fibroblasts from rb-/- mice and exhibited an intermediate ability to inhibit DNA synthe sis in rb+/- as compared with rb+/+ cells, We further found that the BRCA1 protein complexes with the hypophosphorylated form of pRb, This binding is localized to amino acids 304-394 of BRCA1 protein and requires the ABC doma in of pRb. In-frame deletion of BRCA1 fragment involved in interaction with pRb completely abolished the growth-suppressive property of BRCA1. Althoug h it has been reported that BRCA1 interacts with p53, we find the p53 statu s did not affect the ability of BRCA1 to suppress colony formation, Our dat a suggest that the growth suppressor function of BRCA1 depends, at least in part, on Rb.