Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 99 Brookline Avenue, RN-330C, Boston, MA 02115, USA.
Mol Cancer Res. 2010 Mar;8(3):407-20. doi: 10.1158/1541-7786.MCR-09-0403. Epub 2010 Mar 9.
BRCA1 is an essential caretaker protein in the surveillance of DNA damage, is mutated in approximately 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, H(2)O(2) induced the interaction of the nuclear form of beta-catenin with BRCA1. The active form of beta-catenin protein was downregulated upon exposure to H(2)O(2) 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.
BRCA1 是 DNA 损伤监测的必需看守蛋白，在大约 50%的遗传性乳腺癌病例中发生突变，其表达在散发性乳腺癌中经常降低。β-连环蛋白是一种多功能蛋白，与 E-钙粘蛋白、α-连环蛋白和肌动蛋白形成黏附复合物，通过其核转位和激活 β-连环蛋白反应基因，在 Wnt 信号通路中发挥核心作用。尽管在理解 Wnt/β-连环蛋白和 BRCA1 信号级联方面已经取得了重大进展，但尚不清楚β-连环蛋白和 BRCA1 之间是否存在联系。我们观察到，与散发性乳腺癌（14 个样本）和正常乳腺组织相比，大多数 BRCA1 家族性乳腺癌组织（17 例）中细胞核中活性核形式的β-连环蛋白（也称为 ABC、Ser37/Thr41-非磷酸化β-连环蛋白、去磷酸化β-连环蛋白）的表达较低或缺失。野生型 BRCA1 而非突变型 BRCA1 与β-连环蛋白相互作用，并增加体外β-连环蛋白蛋白表达水平。此外，H2O2 诱导核形式的β-连环蛋白与 BRCA1 的相互作用。在 BRCA1 缺陷 HCC1937 乳腺癌细胞的细胞核中暴露于 H2O2 时，β-连环蛋白的活性形式下调，而在 HCC1937 细胞中重建 WT-BRCA1 抑制了这种下调。这项研究提供了 BRCA1 和β-连环蛋白之间存在新的相互作用的证据，并且 BRCA1 的缺失导致核形式的β-连环蛋白表达受损，这可能有助于乳腺癌的发病机制。
