A BRCA1 MUTANT ALTERS G(2)-M CELL-CYCLE CONTROL IN HUMAN MAMMARY EPITHELIAL-CELLS

Mutations in BRCA1 increase the risk of breast and ovarian cancer, Alt hough the mechanism by which mutant BRCA1 alters growth regulation is unknown, the COOH terminus of BRCA1 appears to play a critical role, T o examine this, we introduced a vector expressing BRCA1 COOH-terminal residues 1293-1863 (CT-BRCA1) into nontumorigenic human breast epithel ial cells, Overexpression of CT-BRCA1 led to a reduction in the doubli ng time (from 64 to 44 h) and a decreased reliance on growth factors, suggesting that this CT-BRCA1 may function in a dominant-negative mann er, Expression of CT-BRCA1 induced alterations in cell cycle control, mainly in G(2)-M, including a loss of G(2)-M block by colchicine. Thes e results suggest that one function of BRCA1-related growth control oc curs by governing checkpoint(s) between DNA replication and mitosis.