Wild-Type BRCA1, but not Mutated BRCA1, Regulates the Expression of the Nuclear Form of β-Catenin

BRCA1 is an essential caretaker protein in the surveillance of DNA damage, is mutated in similar to 50% of all hereditary breast cancer cases, and its expression is frequently decreased in sporadic breast cancer. beta-Catenin is a multifunctional protein that forms adhesion complex with E-cadherins, alpha-catenin, and actin, and plays a central role in Wnt signaling through its nuclear translocation and activation of beta-catenin-responsive genes. Although significant progress has been made in understanding the Wnt/beta-catenin and BRCA1 signaling cascades, it is not known whether there is a link between beta-catenin and BRCA1. We observed that the expression of the active nuclear form of beta-catenin (also known as ABC, Ser37/Thr41-nonphosphorylated beta-catenin, dephosphorylated beta-catenin) was lower or absent in the nucleus in most BRCA1 familial breast cancer tissues (17 cases) compared with sporadic breast cancer (14 samples) and normal breast tissues. Wild-type-BRCA1, but not mutated BRCA1, interacted with beta-catenin and increased the levels of beta-catenin protein expression in vitro. Furthermore, H2O2 induced the interaction of the nuclear form of beta-catenin with BRCA1. The active form of beta-catenin protein was downregulated upon exposure to H2O2 in the nucleus of BRCA1-deficient HCC1937 breast cancer cells, whereas reconstitution of WT-BRCA1 in HCC1937 cells inhibited this downregulation. This study provides evidence of a novel interaction between BRCA1 and beta-catenin, and that loss of BRCA1 leads to impaired expression of the nuclear form of beta-catenin, which may contribute to the pathogenesis of breast cancer. Mol Cancer Res; 8(3); 407-20. (C)2010 AACR.