The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1.
The identification of tumorigenic missense mutations within BRCA1 that impair the formation of BARD1-BRCA1 complexes, and of BARD1 mutations in breast carcinomas, sustain the view that BARD1 is involved in BRCA1-mediated tumor suppression.
We now show that these autoantibodies are directed against BARD1, originally identified as a protein interacting with the product of the breast cancer gene 1, BRCA1.
Because BARD1 associates via its NH2-terminal RING domain with the breast cancer susceptibility gene BRCA1 that provides a platform for interactions with proteins involved in DNA repair and checkpoint control, our results provide a link between the Ewing's sarcoma gene product and the genome surveillance complex.
Here, we observe that purified RINGs from a variety of functionally unrelated proteins, including promyelocytic leukemia protein, KAP-1TIF1beta, Z, Mel18, breast cancer susceptibility gene product 1 (BRCA1), and BRCA1-associated RING domain (BARD1), self-assemble into supramolecular structures in vitro that resemble those they form in cells.
Our results support the hypothesis that the differential gene expression of TIEG, Smad2, and Bard1, which are tumor suppressor genes, plays a significant role in the proliferation of breast cancer.
These results suggest that the contribution of the BARD1 germline variants to breast cancer predisposition is very limited, and that neither Cys557Ser nor Val507Met have an effect on familial breast cancer susceptibility.
The N-terminus of the Breast Cancer-1 predisposition protein (BRCA1) associates with the BRCA1-associated RING domain-1 protein (BARD1) to form a heterodimer, which exhibits ubiquitin ligase activity that is abrogated by known cancer-associated BRCA1 missense mutations.
BARD1 is indispensable for cell viability, so loss-of-function mutations are rare, but mutations and truncations that alter its function might be involved in the pathogenesis of breast cancer.
Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer.
These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.
Using DHPLC analysis we screened the coding region of BARD1 for variants in 210 probands of breast cancer families including 129 families with no mutations in BRCA1 or BRCA2.
Our data imply a critical role of UBE2T in development and/or progression of breast cancer through the interaction with and the regulation of the BRCA1/BARD1 complex.
A blood test based on BARD1, a protein that interacts with the breast cancer gene product BRCA1, is a promising candidate for fulfilling these conditions.
The breast cancer susceptibility gene BARD1 (BRCA1-associated RING domain protein, MIM# 601593) acts with BRCA1 in DNA double-strand break (DSB) repair and also in apoptosis initiation.