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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been over a decade since mutations in BRCA1 and BRCA2 were found to be associated with a small number of familial breast cancer cases. BRCA1 is a large protein that interacts with many other proteins that have diverse functions, so it has been a challenge to determine how defects in its function could lead to cancer. One particular protein, BARD1, seems to be an important regulator of the tumour-suppressor function of BRCA1, as well as acting as a tumour suppressor itself. 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.
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PMID:Is there more to BARD1 than BRCA1? 1663 66

We have previously reported the identification and characterization of a novel BRCA1/2 interacting protein complex, BRCC (BRCA1/2-containing complex). BRCC36, one of the proteins in BRCC, directly interacts with BRCA1, and regulates the ubiquitin E3 ligase activity of BRCC. Importantly, BRCC36 is aberrantly expressed in the vast majority of breast tumors, indicating a potential role in the pathogenesis of this disease. To further elucidate the functional consequence of abnormal BRCC36 expression in breast cancer, we have done in vivo silencing studies using small interfering RNAs targeting BRCC36 in breast cancer cell lines, i.e., MCF-7, ZR-75-1, and T47D. Knock-down of BRCC36 alone does not affect cell growth, but when combined with ionizing radiation (IR) exposure, it leads to an increase in the percentage of cells undergoing apoptosis when compared with the small interfering RNA control group in breast cancer cells. Immunoblot analysis shows that inhibition of BRCC36 has no effect on the activation of ATM, expression of p21 and p53, or BRCA1-BARD1 interaction following IR exposure. Importantly, BRCC36 depletion disrupts IR-induced phosphorylation of BRCA1. Immunofluorescent staining of BRCA1 and gamma-H2AX indicates that BRCC36 depletion prevents the formation of BRCA1 nuclear foci in response to DNA damage in breast cancer cells. These results show that down-regulation of BRCC36 expression impairs the DNA repair pathway activated in response to IR by inhibiting BRCA1 activation, thereby sensitizing breast cancer cells to IR-induced apoptosis.
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PMID:BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation. 1670 25

The BRCA1 Associated RING Domain (BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common (minor allele frequency (MAF)>0.10) non-synonymous polymorphisms (Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P(int )= 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor (PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.
Breast Cancer Res Treat 2007 May
PMID:Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis. 1702 82

We have used a chromatin immunoprecipitation (ChIP)-based cloning strategy to isolate and identify genes associated with estrogen receptor alpha (ERalpha) in MCF-7 human breast cancer cells. One of the gene regions isolated was a 288bp fragment from the ninth intron of the breast cancer 1 associated ring domain (BARD1) gene. We demonstrated that ERalpha associated with this region of the endogenous BARD 1 gene in MCF-7 cells, that ERalpha bound to three of five ERE half sites located in the 288bp BARD1 region, and that this 288bp BARD1 region conferred estrogen responsiveness to a heterologous promoter. Importantly, treatment of MCF-7 cells with estrogen increased BARD1 mRNA and protein levels. These findings demonstrate that ChIP cloning strategies can be utilized to successfully isolate regulatory regions that are far removed from the transcription start site and assist in identifying cis elements involved in conferring estrogen responsiveness.
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PMID:Estrogen receptor alpha regulates expression of the breast cancer 1 associated ring domain 1 (BARD1) gene through intronic DNA sequence. 1727 94

The breast cancer suppressor protein, BRCA1, is a ubiquitin ligase expressed in a wide range of tissues. However, inheritance of a single BRCA1 mutation significantly increases a woman's lifetime chance of developing tissue-specific cancers in the breast and ovaries. Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor alpha (ERalpha) transcriptional activation by BRCA1. Here, we show that ERalpha is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ERalpha activity by BRCA1. Our results show ERalpha is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ERalpha ubiquitination include the RING domains and at least 241 and 170 residues of BRCA1 and BARD1, respectively. Cancer-predisposing mutations in BRCA1 are observed to abrogate ERalpha ubiquitination. The identification of ERalpha as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.
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PMID:Estrogen receptor alpha is a putative substrate for the BRCA1 ubiquitin ligase. 1739 32

BARD1 (BRCA1-associated RING domain) is the dominant binding partner of BRCA1 in vivo. The BARD1 gene has been reported to be mutated in a subset of breast and ovarian cancer patients and BARD1 germ-line mutations have been identified in breast cancer patients negative for BRCA1 or BRCA2 gene alterations. In the present study, we show by RT-PCR and direct sequencing analysis the occurrence of seven novel and one previously identified BARD1 splicing variants in human lymphocytes and breast cancers. Two of the eight variants (BARD1delta and BARD1 DeltaRIN) preserve a correct open reading frame and could encode BARD1 internally deleted proteins, while the remaining six variants display premature stop codons. Characterization of the relative expression of BARD1 FL, BARD1delta, and BARD1 DeltaRIN using quantitative PCR analysis indicated that the mean expression levels of BARD1 FL, BARD1delta, and BARD1 DeltaRIN were significantly higher in tumors than in morphologically normal tissues and lymphocytes. However, we were unable to identify either qualitatively or quantitatively tumor-specific expression patterns of the identified BARD1 splicing variants.
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PMID:Identification of novel alternatively spliced BRCA1-associated RING domain (BARD1) messenger RNAs in human peripheral blood lymphocytes and in sporadic breast cancer tissues. 1749 50

The breast cancer regulatory protein-1 (BRCA1)-associated RING domain 1 (BARD1) gene is mutated in a subset of breast/ovarian cancers. BARD1 functions as a heterodimer with BRCA1 in nuclear DNA repair. BARD1 also has a BRCA1-independent apoptotic activity. Here we investigated the link between cytoplasmic localization and apoptotic function of BARD1. We used immunofluorescence microscopy and deconvolution analysis to resolve BARD1 cytoplasmic staining patterns and detected endogenous BARD1 at mitochondria. BARD1 was also detected in mitochondrial cell fractions by immunoblotting. The targeting of BARD1 to mitochondria was modestly stimulated by DNA damage and did not require BRCA1 as indicated by RNA interference and peptide-competition experiments. Transiently expressed yellow fluorescence protein-BARD1 localized to mitochondria, and the targeting sequences were mapped to both the N and C terminus of BARD1. Ectopic yellow fluorescence protein-BARD1 induced apoptosis and loss of mitochondrial membrane potential in MCF-7 breast tumor cells. BARD1 apoptotic function was associated with stimulation of Bax oligomerization at mitochondria. This distinguishes it from BRCA1, which is pro-apoptotic but did not induce Bax oligomerization. The cancer-associated BARD1 splice-variant DeltaRIN (lacks the BRCA1 binding domain and ankyrin repeats) was recruited to mitochondria but did not stimulate apoptosis or alter membrane permeability. We propose that BARD1 has two main sites of action in its cellular response to DNA damage, the nucleus, where it promotes cell survival through DNA repair, and the mitochondria, where BARD1 regulates apoptosis.
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PMID:BARD1 translocation to mitochondria correlates with Bax oligomerization, loss of mitochondrial membrane potential, and apoptosis. 1751 55

Mutations affecting the BRCT domains of the breast cancer-associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-gammaH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.
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PMID:RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. 1752 26

BRCA1 is a tumor suppressor involved in the maintenance of genome integrity. BRCA1 co-localizes with DNA repair proteins at nuclear foci in response to DNA double-strand breaks caused by ionizing radiation (IR). The response of BRCA1 to agents that elicit DNA single-strand breaks (SSB) is poorly defined. In this study, we compared chemicals that induce SSB repair and observed the most striking nuclear redistribution of BRCA1 following treatment with the alkylating agent methyl methanethiosulfonate (MMTS). In MCF-7 breast cancer cells, MMTS induced movement of endogenous BRCA1 into distinctive nuclear foci that co-stained with the SSB repair protein XRCC1, but not the DSB repair protein gamma-H2AX. XRCC1 did not accumulate in foci after ionizing radiation. Moreover, we showed by deletion mapping that different sequences target BRCA1 to nuclear foci induced by MMTS or by ionizing radiation. We identified two core MMTS-responsive sequences in BRCA1: the N-terminal BARD1-binding domain (aa1-304) and the C-terminal sequence aa1078-1312. These sequences individually are ineffective, but together they facilitated BRCA1 localization at MMTS-induced foci. Site-directed mutagenesis of two SQ/TQ motif serines (S1143A and S1280A) in the BRCA1 fusion protein reduced, but did not abolish, targeting to MMTS-inducible foci. This is the first report to describe co-localization of BRCA1 with XRCC1 at SSB repair foci. Our results indicate that BRCA1 requires BARD1 for targeting to different types of DNA lesion, and that distinct C-terminal sequences mediate selective recruitment to sites of double- or single-strand DNA damage.
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PMID:Identification of sequences that target BRCA1 to nuclear foci following alkylative DNA damage. 1753 42

Human papillomaviruses (HPVs), which are associated with the majority of cervical cancers, encode a transforming protein, E6, which interacts with the p53 tumor suppressor protein. There is a wide effort focused on searching for the target of the involvement of p53-independent HPV 16 E6-interacting proteins. We identified Breast Cancer 1 Gene (BRCA1)-associated ring domain protein 1 (BARD1) as a binding partner of E6 and investigated its biological function in cervical cancer cells. In vivo co-immunoprecipitation assay was performed to determine whether E6-BARD1 interaction occurred. We then used a degradation assay to determine whether E6-mediated inactivation of BARD1 transactivation function was associated with BARD1 degradation. A mutation assay revealed the site of interaction of E6 with BARD1. The effect of BARD1 on p53 transcriptional activity was tested using BARD1 knockdown and overexpression systems. BARD1 was not degraded by E6, and, instead, formed a physical complex with E6. Moreover, the mutations of the metal motif zinc-finger region decreased the ability of E6 to interact with BARD1. Transient transfection of BARD1 increased the p53-mediated activation of p21(WAF1) promoter despite the presence of E6. Additionally, the existence of BARD1 inactivated the expression of E6 in cervical cancer cells. These findings suggest that BARD1 may regulate the transcriptional activities of p53 as tumor suppressors.
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PMID:Novel interaction between HPV E6 and BARD1 (BRCA1-associated ring domain 1) and its biologic roles. 1767 35


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