A BRCA1 mutant alters G2-M cell cycle control in human mammary epithelial cells.

Mutations in BRCA1 increase the risk of breast and ovarian cancer. Although the mechanism by which mutant BRCA1 alters growth regulation is unknown, the COOH terminus of BRCA1 appears to play a critical role. To examine this, we introduced a vector expressing BRCA1 COOH-terminal residues 1293-1863 (CT-BRCA1) into nontumorigenic human breast epithelial cells. Overexpression of CT-BRCA1 led to a reduction in the doubling time (from 64 to 44 h) and a decreased reliance on growth factors, suggesting that this CT-BRCA1 may function in a dominant-negative manner. Expression of CT-BRCA1 induced alterations in cell cycle control, mainly in G2-M, including a loss of G2-M block by colchicine. These results suggest that one function of BRCA1-related growth control occurs by governing checkpoint(s) between DNA replication and mitosis.