Wild-type BRCA1, but not mutated BRCA1, regulates the expression of the nuclear form of beta-catenin.
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.
Li
Huchun
H
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 99 Brookline Avenue, RN-330C, Boston, MA 02115, USA.
Sekine
Masayuki
M
Tung
Nadine
N
Avraham
Hava Karsenty
HK
D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016877:Oxidants; D051176:beta Catenin; D006861:Hydrogen Peroxide