Breast cancer susceptibility gene 1 (BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination.
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.
BARD1Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC.
BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347).
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.
After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88).
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.
BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with 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.
CircRNA_BARD1 (circ_0001098) was up-regulated in breast cancer with the treatment of TCDD and the up-regulation of circRNA_BARD1 could restrain cell proliferation, block cell cycle and promote cell apoptosis.
For example, several sex-ratio genes were found to interact with brc-1 and brd-1, the orthologs of the human breast cancer genes BRCA1 and BARD1, respectively.
Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk.
Furthermore, the BARD1Cys557Ser allele does not appear to modify the risk of breast cancers among carriers of BRCA1 mutations, or of other predisposing mutations.
Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians.
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.