Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The Arabidopsis (Arabidopsis thaliana) orthologs of Brca2, a protein whose mutations are involved in breast cancer in humans, were previously shown to be essential at meiosis. In an attempt to better understand the Brca2-interacting properties, we examined four partners of the two isoforms of Brca2 identified in Arabidopsis (AtRad51, AtDmc1, and two AtDss1 isoforms). The two Brca2 and the two Dss1 isoforms are named AtBrca2(IV), AtBrca2(V), AtDss1(I), and AtDss1(V) after their chromosomal localization. We first show that both AtBrca2 proteins can interact with either AtRad51 or AtDmc1 in vitro, and that the N-terminal region of AtBrca2 is responsible for these interactions. More specifically, the BRC motifs (so called because iterated in the Brca2 protein) in Brca2 are involved in these interactions: BRC motif number 2 (BRC2) alone can interact with AtDmc1, whereas BRC motif number 4 (BRC4) recognizes AtRad51. The human Rad51 and Dmc1 proteins themselves can interact with either the complete (HsRad51) or a shorter version of AtBrca2 (HsRad51 or HsDmc1) that comprises all four BRC motifs. We also identified two Arabidopsis isoforms of Dss1, another known partner of Brca2 in other organisms. Although all four Brca2 and Dss1 proteins are much conserved, AtBrca2(IV) interacts with only one of these AtDss1 proteins, whereas AtBrca2(V) interacts with both of them. Finally, we show for the first time that an AtBrca2 protein could bind two different partners at the same time: AtRad51 and AtDss1(I), or AtDmc1 and AtDss1(I).
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PMID:Interaction between Arabidopsis Brca2 and its partners Rad51, Dmc1, and Dss1. 1641 10

A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form colocalizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2DeltaCTD), and disrupted the FANCC gene in this background. The fancc/brca2DeltaCTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2DeltaCTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights into the functional interplay between the classical FA pathway and BRCA2.
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PMID:Functional interplay between BRCA2/FancD1 and FancC in DNA repair. 1668 15

In this study, the genetic polymorphisms associated with breast cancer in southern Taiwan were investigated. Two categories of genes were analyzed: (1) BRCA1, BRCA2, and Rad51, the DNA repair factors involved in homologous recombinational repair; and (2) CYP1A1, COMT, GST, and NAT2, the xenobiotic-metabolizing enzymes (XME) involved in estrogen metabolism. We found that the number of deletions and/or mutations in the GST genes was highly correlated with the occurrence of breast cancer. These data suggest that the GST enzymes, which detoxify the catechol estrogen quinones, are important target molecules for screening in populations at high risk of breast cancer.
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PMID:Glutathione S-transferase polymorphisms associated with risk of breast cancer in southern Taiwan. 1671 66

Abnormal regulation of progression from G(1) to S phase of the cell cycle by altered activity of cyclin-dependent kinases (CDKs) is a hallmark of cancer. However, inhibition of CDKs, particularly CDK2, has not shown selective activity against most cancer cells because the kinase seems to be redundant in control of cell cycle progression. Here, we show a novel role in the DNA damage response and application of CDK inhibitors in checkpoint-deficient cells. CDK2(-/-) mouse fibroblasts and small interfering RNA--mediated or small-molecule--mediated CDK2 inhibition in MCF7 or U2OS cells lead to delayed damage signaling through Chk1, p53, and Rad51. This coincided with reduced DNA repair using the single-cell comet assay and defects observed in both homologous recombination and nonhomologous end-joining in cell-based assays. Furthermore, tumor cells lacking cancer predisposition genes BRCA1 or ATM are 2- to 4-fold more sensitive to CDK inhibitors. These data suggest that inhibitors of CDK2 can be applied to selectively enhance responses of cancer cells to DNA-damaging agents, such as cytotoxic chemotherapy and radiotherapy. Moreover, inhibitors of CDKs may be useful therapeutics in cancers with defects in DNA repair, such as mutations in the familial breast cancer gene BRCA1.
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PMID:Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. 1691 1

The breast cancer susceptibility protein, Brca2 and the RecQ helicase, Blm (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through homologous recombination (HR). Brca2 facilitates HR by interacting with Rad51 in multiple regions, the BRC motifs encoded by exon 11 and a single domain encoded by exon 27; however, the exact importance of these regions is not fully understood. Blm also interacts with Rad51 and appears to suppress HR in most circumstances; however, its yeast homologue Sgs1 facilitates HR in response to some genotoxins. To better understand the biological importance of these two proteins, we performed a genotoxic screen on mouse embryonic stem (ES) cells impaired for either Brca2 or Blm to establish their genotoxic profiles (a cellular dose-response to a wide range of agents). This is the first side-by-side comparison of these two proteins in an identical genetic background. We compared cells deleted for Brca2 exon 27 to cells reduced for Blm expression and find that the Brca2- and Blm-impaired cells exhibit genotoxic profiles that reflect opposing activities during HR. Cells deleted for Brca2 exon 27 are hypersensitive to gamma-radiation, streptonigrin, mitomycin C and camptothecin and mildly resistant to ICRF-193 which is similar to HR defective cells null for Rad54. By contrast, Blm-impaired cells are hypersensitive to ICRF-193, mildly resistant to camptothecin and mitomycin C and more strongly resistant to hydroxyurea. These divergent profiles support the notion that Brca2 and Blm perform opposing functions during HR in mouse ES cells.
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PMID:Embryonic stem cells deficient for Brca2 or Blm exhibit divergent genotoxic profiles that support opposing activities during homologous recombination. 1699 31

Radiotherapy and chemotherapy often induce DNA double-strand breaks in both normal and malignant cells. The proteins involved in the repair of such lesions are central to cancer prognosis and treatment, as they can be overexpressed in many cancers, accelerating malignant transformation and increasing repair capacity, potentially leading to cellular resistance. If malignant cells can be selectively targeted repair proteins could also be candidates for targeted therapy. In this study, two keyplayers in eukaryotic DNA double-strand break repair, Rad51 and DNA-dependent protein kinase catalytic subunit, were analysed in noncancerous human breast cells (MCF12A) and the breast cancer cell lines (MDA MB 231 and MCF7) in response to treatment with doxorubicin. A cell cycle-independent increase in Rad51 protein levels (a recombinase involved in homologous recombination repair) was observed 24 and 48 h after treatment in MDA MB 231 and MCF12A when exposed to low levels of doxorubicin, whereas MCF7 cells displayed a continuous decrease in Rad51 protein with increasing drug concentration. DNA-dependent protein kinase catalytic subunit, which is involved in nonhomologous end joining of DNA lesions, remained unaltered under all conditions tested. Topoisomerase II-alpha protein, the primary target of doxorubicin, was upregulated at low concentrations of doxorubicin in all cell lines tested. Here we show that Rad51 protein levels can be differentially regulated in normal and malignant breast cell lines in response to doxorubicin, independent of cell cycle state. These observations have direct relevance to chemosensitivity and add an additional prognostic factor that could be taken into account when designing targeted therapeutic regimes.
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PMID:Differential regulation of DNA repair protein Rad51 in human tumour cell lines exposed to doxorubicin. 1735 94

The human Rad51 protein (HsRad51) catalyzes homologous pairing and strand exchange between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) during recombinational repair of double-stranded DNA breaks. An HsRad51 mutation that results in the substitution of Gln for Arg150 (R150Q) was found in bilateral breast cancer patients; however, the consequences of this R150Q mutation have not been elucidated. To determine how this HsRad51(R150Q) mutation affects HsRad51 function, in the present study, we purified the HsRad51(R150Q) mutant. The purified HsRad51(R150Q) was completely proficient in the ATP-hydrolyzing activity. A gel filtration analysis revealed that HsRad51(R150Q) also retained the polymer formation ability. In contrast, the ssDNA- and dsDNA-binding abilities of HsRad51(R150Q) were clearly reduced, as compared to those of HsRad51. These differences in the DNA-binding properties between HsRad51(R150Q) and HsRad51 may be important to account for the tumorigenesis in breast cancer patients with the HsRad51(R150Q) mutation.
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PMID:Altered DNA binding by the human Rad51-R150Q mutant found in breast cancer patients. 1766 88

Defects in Brca1 confer susceptibility to breast cancer and genomic instability indicative of aberrant repair of DNA breaks. Brca1 was previously implicated in the homologous recombination pathway via effects on the assembly of recombinase Rad51. Activation-induced cytidine deaminase (AID) deaminates C to U in B lymphocyte immunoglobulin (Ig) DNA to initiate programmed DNA breaks. Subsequent uracil-glycosylase mediated U removal, and perhaps further processing, leads to four known classes of mutation: Ig class switch recombination that results in a region-specific genomic deletion, Ig somatic hypermutation that introduces point mutations in Ig V-regions, Ig gene conversion in vertebrates that possess Ig pseudo-V genes, and translocations common to B cell lymphomas. We tested the involvement of Brca1 in AID-dependent Ig diversification in chicken DT40 cells. The DT40 cell line diversifies IgVlambda mainly by gene conversion, and less so by point mutation. Brca1-deficiency caused a shift in Vlambda diversification, significantly reducing the proportion of gene conversions relative to point mutations. Thus, Brca1 regulates AID-dependent DNA lesion repair. Interestingly, while Brca1 is required to recruit ubiquitinated FancD2 to DNA damage, the phenotype of Brca1-deficient DT40 differs from the one of FancD2-deficient DT40, in which both gene conversion and non-templated mutations are impaired.
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PMID:Brca1 in immunoglobulin gene conversion and somatic hypermutation. 1803 97

In the decade since the BRCA1 and BRCA2 genes were cloned, much has been learned about the function of these two major causes of familial breast cancer. BRCA2 has been shown to play a direct role in the repair of DNA by homologous recombination, by interacting with the Rad51 protein and facilitating the formation of Rad51 aggregates at the site of DNA damage. It likely plays a similar role when double strand breaks are created in the course of normal DNA replication; the absence of BRCA2 results in chromosomal instability, which is likely secondary to the defect in DNA repair. In the absence of BRCA2, the cell is more dependent on residual repair via Rad52, which makes Rad52 a target for therapy in BRCA-deficient tumors. BRCA1 plays a role in sensing DNA damage and replication stress and mediating the signaling responses. Therefore, in addition to its role in mediating DNA repair by homologous recombination via BRCA2, it can also signal cell cycle checkpoints and mediate other transcriptional responses to DNA damage. We have argued that the mechanism of cancer susceptibility from BRCA1 or BRCA2 deficiency is mediated via the defect in homologous recombination, since it is the main feature they share in common. We and others have recently demonstrated that the defect in homologous recombination changes the drug sensitivity profile, rendering the BRCA-deficient breast cancers sensitive to MitomycinC, cisplatin, etoposide and other drugs that produce complex double-stranded lesions in DNA. Furthermore, they show resistance to taxanes and navelbine. Fanconi anemia defective cells also show sensitivity to the same class of drugs, although their defect in homologous recombination in response to strand breaks appears less marked than in BRCA-deficient cells. However, Fanconi anemia cells also show chromosomal fragility, and appear to have defects in maintenance of the replication fork. Therefore, knowledge of whether this specific DNA repair pathway of homologous recombination is defective in breast cancer cells would be valuable information in planning optimized individual therapy. We have developed techniques to measure the functional integrity of homologous recombination in human breast cancers. Core biopsy samples are obtained and immediately irradiated ex vivo, allowing 3-4 hours for the appearance of Rad51, BRCA1 and FancD2 foci. Thin sections are obtained, permeabilized and stained by immunofluorescent techniques. We have identified tumors with defects in the ability to form Rad51 and BRCA1 foci, where there is no known genetic predisposition, implying that this BRCA-dependent repair pathway may be inactivated in sporadic as well as familial breast cancers. Thus, functional assays of homologous recombination could become a useful technique to determine phenotype of human breast cancer, which in turn will influence the choice of therapy.
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PMID:Therapeutic exploitation of tumor cell defects in homologous recombination. 1847 29

The epidermal growth factor receptor (EGFR) family has been implicated in several cancers, including breast, and its members have become the target of novel cancer therapies. In this report, we show a novel link between erlotinib, a potent EGFR inhibitor, DNA damage, and homology-directed recombinational repair (HDR) in human breast cancer cells. Erlotinib suppresses HDR. This is not secondary to erlotinib-mediated changes in cell cycle and is associated with increased gamma-H2AX foci, which is an in situ marker of chromosomal double-strand breaks. Both Rad51 and BRCA1 are essential components of the HDR machinery. Consistent with decreased HDR in erlotinib-treated cells, erlotinib also attenuates DNA damage-induced Rad51 foci and results in cytoplasmic retention of BRCA1. As BRCA1 is a shuttling protein and its nuclear function of promoting HDR is controlled by its subcellular localization, we further show that targeted translocation of BRCA1 to the cytoplasm enhances erlotinib sensitivity. These findings suggest a novel mechanism of action of erlotinib through its effects on the BRCA1/HDR pathway. Furthermore, BRCA1/HDR status may be an innovative avenue to enhance the sensitivity of cancer cells to erlotinib.
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PMID:Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells. 1901 Aug 85


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