Research IndicatorsGraph generated 12 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ZNF350 (cancer-related)
Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial-mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
Inactivation or mutation of the VHL gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). In the present study, we identified ZBRK1 as a novel VHL interacting protein by yeast two-hybrid screening, and found a single ZBRK1-binding site located in the VHL promoter region. Ectopic expression of ZBRK1 increases transcriptional activity of the VHL, whereas the depletion of endogenous ZBRK1 by shRNA leads to reduction of VHL expression. We also demonstrate that the inhibition of VEGF transcription by ZBRK1 overexpression is dependent on VHL/HIF pathway. Moreover, VHL is confirmed to serve as a bridge component for the association of ZBRK1 and p300, which leads to an increase in ZBRK1 transcriptional activity in the VHL promoter. We further provide striking evidences that ZBRK1 acts as a tumor suppressor in renal carcinoma by a variety of in vitro and in vivo assays, and ZBRK1 may represent a molecular marker to distinguish patients with ccRCC at high risk from those with a better survival prognosis. Taken together, these findings suggest that ZBRK1 suppresses renal cancer progression perhaps by regulating VHL expression.
KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2, and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer.
Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.
Calderon MR, Verway M, Benslama RO, et al.Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1.
Nucleic Acids Res. 2014; 42(11):7012-27 [PubMed
] Free Access to Full Article Related Publications
We identified a novel interaction between ligand-dependent corepressor (LCoR) and the corepressor KRAB-associated protein-1 (KAP-1). The two form a complex with C2H2 zinc-finger transcription factor ZBRK1 on an intronic binding site in the growth arrest and DNA-damage-inducible α (GADD45A) gene and a novel site in the fibroblast growth factor 2 (FGF2) gene. Chromatin at both sites is enriched for histone methyltransferase SETDB1 and histone 3 lysine 9 trimethylation, a repressive epigenetic mark. Depletion of ZBRK1, KAP-1 or LCoR led to elevated GADD45A and FGF2 expression in malignant and non-malignant breast epithelial cells, and caused apoptotic death. Loss of viability could be rescued by simultaneous knockdowns of FGF2 and transcriptional coregulators or by blocking FGF2 function. FGF2 was not concurrently expressed with any of the transcriptional coregulators in breast malignancies, suggesting an inverse correlation between their expression patterns. We propose that ZBRK1, KAP-1 and LCoR form a transcriptional complex that silences gene expression, in particular FGF2, which maintains breast cell viability. Given the broad expression patterns of both LCoR and KAP-1 during development and in the adult, this complex may have several regulatory functions that extend beyond cell survival, mediated by interactions with ZBRK1 or other C2H2 zinc-finger proteins.
Roughly two-thirds of all breast cancers are ERα-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ERα-positive TMX2-11 had 4000 hypermethylated sites and ERα-negative TMX2-28 had over 33 000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2ꞌdeoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome.
ZBRK1, a zinc finger protein that interacts with breast cancer 1 (BRCA1) and KRAB-ZFP-associated protein 1 (KAP1), has been suggested to serve as a tumor suppressor via repression of tumor metastasis/invasion. To date, the detailed molecular mechanisms for how BRCA1 and KAP1 participate in ZBRK1-mediated transcriptional repression, metastasis and invasion as well as the associated clinical relevance remain unclear. In this study, we demonstrated that both the N- and C-terminal domains of ZBRK1 are important for inhibiting cell proliferation and anchorage-independent growth in cervical cancer. Specifically, the N-terminal KRAB domain of ZBRK1 displayed a more crucial role in inhibiting metastasis and invasion through modulation of KAP1 function in a transcriptionally dependent manner. The loss of ZBRK1 results in an increase of KAP1 expression, which enhanced migration and invasion of cervical cancer cells both the in vitro and in vivo. Moreover, an inverse correlation of expression levels was observed between ZBRK1 and KAP1 following tumor progression from in situ carcinoma to invasive/metastatic cervical cancer specimens. Taken together, the current results indicate that a loss of ZBRK1 contributes to the increased expression of KAP1, potentiating its role to enhance metastasis and invasion.
The gene Oct4 encodes a transcription factor critical for the maintenance of pluripotency and self-renewal in embryonic stem cells. In addition, improper re-activation of Oct4 contributes to oncogenic processes. Herein, we describe a novel designer zinc finger protein (ZFP) capable of upregulating the endogenous Oct4 promoter in a panel of breast and ovarian cell lines carrying a silenced gene. In some ovarian tumor lines, the ZFP triggered a strong reactivation of Oct4, with levels of expression comparable with exogenous Oct4 cDNA delivery. Surprisingly, the reactivation of Oct4 required a KRAB domain for effective upregulation of the endogenous gene. While KRAB-containing ZFPs are traditionally described as transcriptional repressors, our results suggest that these proteins could, in certain genomic contexts, function as potent activators and, thus, outline an emerging novel function of KRAB-ZFPs. In addition, we document a novel ZFP that could be used for the epigenetic reprograming of cancer cells.
Plourde KV, Labrie Y, Desjardins S, et al.Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families.
J Hum Genet. 2013; 58(2):59-66 [PubMed
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ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%. However, based on their frequency observed in breast cancer and unrelated healthy individuals, these are not statistically associated with breast cancer risk. Luciferase promoter assays in two breast cancer cell lines identified two haplotypes (H11 and H12) stimulating significantly the expression of ZNF350 transcript compared with the common haplotype H8. The high expression of the H11 allele was associated with the variant c.-874A. Using MatInspector and Transcription Element Search softwares, in silico analyses predicted that the variant c.-874A created a binding site for the factors c-Myc and myogenin. This study represents the first characterization step of the ZNF350 promoter. Additional studies in larger cohorts and other populations will be needed to further evaluate whether common and/or rare ZNF350 promoter variants and haplotypes could be associated with a modest risk of breast cancer.
Hallen L, Klein H, Stoschek C, et al.The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates SCA2 gene transcription through direct interaction with its gene product, ataxin-2.
Hum Mol Genet. 2011; 20(1):104-14 [PubMed
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Gene transcription is controlled by transcriptional regulators acting with specific co-regulators to allow gene activation and repression. Here, we report the identification of the KRAB-containing zinc-finger transcriptional regulator, ZBRK1, as an interaction partner of the SCA2 gene product ataxin-2. Furthermore, we discovered that an elevated ZBRK1 level resulted in increased ataxin-2 levels, whereas interference on transcriptional and protein levels of ZBRK1 yielded reduced ataxin-2 levels, suggesting that a complex comprising ZBRK1 and ataxin-2 regulates SCA2 gene transcription. A bioinformatic analysis utilizing the known ZBRK1 consensus DNA-binding motif revealed ZBRK1-binding sites in the SCA2 promoter. These predicted sites were experimentally validated by chromatin-immunoprecipitation experiments along with luciferase-based promoter analyses corroborating that SCA2 gene transcription is controlled by a ZBRK1/ataxin-2 complex. Finally, we demonstrate that SCA2 gene transcription is significantly reduced in colon tumors possessing low ZBRK1 transcripts. Thus, our results provide first evidence that ataxin-2 acts as a co-regulator of ZBRK1 activating its own transcription, thereby representing the first identified ZBRK1 co-activator.
Yarden RI, Friedman E, Metsuyanim S, et al.Single-nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent.
Mol Carcinog. 2010; 49(6):545-55 [PubMed
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Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2-associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish-Ashkenazi women for functional single-nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53-mediated apoptosis, as well as two tag-SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing lambda(2) and Kaplan-Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44-54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049-7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205-11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289-1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles.
The high mobility group AT-hook 2 (HMGA2), a DNA architectural protein, is highly regulated during development and plays an important role in tumorigenesis. Indeed, HMGA2 was overexpressed in many different kinds of tumors. However, the mechanisms regulating HMGA2 expression remain elusive. Using microarray analysis, we found that HMGA2, along with a dozen of other genes, was co-repressed by ZBRK1, BRCA1, and CtIP. BRCA1 exerts its transcriptional repression activity through interaction with the transcriptional repressor ZBRK1 in the central domain, and with CtIP in the C-terminal BRCT domain. Here, we show that ZBRK1, BRCA1, and CtIP form a repression complex that coordinately regulates HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. Depletion of any of the proteins in this complex via adenoviral RNA interference in MCF10A mammary epithelial cells activates HMGA2 expression, resulting in increased colony formation in soft agar. Similarly, depletion of ZBRK1, or ectopic overexpression of HMGA2, in MCF10A cells induces abnormal acinar size with increased cell number and inhibits normal acinar formation. Consistently, many BRCA1-deficient mouse breast tumors express higher levels of HMGA2 than BRCA1-proficient tumors. These results suggest that activation of HMGA2 gene expression through derepression of the ZBRK1/BRCA1/CtIP complex is a significant step in accelerating breast tumorigenesis.
The BRCA1-interacted transcriptional repressor ZBRK1 has been associated with antiangiogenesis, but direct evidence of a tumor suppressor role has been lacking. In this study, we provide evidence of such a role in cervical carcinoma. ZBRK1 levels in cervical tumor cells were significantly lower than in normal cervical epithelial cells. In HeLa cervical cancer cells, enforced expression inhibited malignant growth, invasion, and metastasis in a variety of in vitro and in vivo assays. Expression of the metalloproteinase MMP9, which is known to be an important driver of invasion and metastasis, was found to be inversely correlated with ZBRK1 in tumor tissues and a target for repression in tumor cells. Our findings suggest that ZBRK1 acts to inhibit metastasis of cervical carcinoma, perhaps by modulating MMP9 expression.
Huo X, Lu C, Huang X, et al.Polymorphisms in BRCA1, BRCA1-interacting genes and susceptibility of breast cancer in Chinese women.
J Cancer Res Clin Oncol. 2009; 135(11):1569-75 [PubMed
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PURPOSE: BRCA1-interacting protein C-terminal helicase 1 (BRIP1) and zinc finger protein 350 (ZNF350) work with BRCA1 in tumor suppression procedures. Low penetrance variants of these three genes may jointly affect individuals' breast cancer susceptibility in general population.
METHODS: We focused on potentially functional single nucleotide polymorphisms (SNPs) in the coding regions of BRIP1, ZNF350 and BRCA1 and pairwise-tagging approach was used to minimize the number of SNPs. Five SNPs were selected and genotyped by PCR-restriction fraction length polymorphism or PCR-primer introduced restriction analysis assays in a case-control study with 568 breast cancer cases and 624 controls in a Chinese population.
RESULTS: All of the five SNPs except rs2278415 of ZNF350 conferred a modestly increased risk, although, with no statistical significance. Joint effect analyses indicated that all the variant genotypes of ZNF350 polymorphisms accounted for increased breast cancer risk among subjects carrying variant homozygote of BRCA1 rs799917, particularly for ZNF350 rs4986773 (OR = 2.03, 95%CI = 1.02-4.05, the test for gene-gene interaction P (int) = 0.059).
CONCLUSION: BRCA1 and ZNF350 may jointly contribute to individuals' susceptibility of breast cancer in Chinese women. Further functional studies are warranted to validate our findings.
Desjardins S, Ouellette G, Labrie Y, et al.Analysis of GADD45A sequence variations in French Canadian families with high risk of breast cancer.
J Hum Genet. 2008; 53(6):490-8 [PubMed
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GADD45A is an evolutionary conserved gene whose expression is regulated by two major tumor suppressor proteins involved in breast cancer etiology, namely, p53 and BRCA1, and which acts primarily in the control of the G2/M cell-cycle transition, apoptosis, and DNA repair. Following genotoxic stress, the p53 protein activates GADD45A transcription, whereas in absence of DNA damage, BRCA1 represses GADD45A expression through interaction with the zinc finger protein ZNF350. Moreover, BRCA1 can activate GADD45A gene expression through interactions with transcription factors binding to the gene promoter. On the basis of the intricate network of interactions between GADD45A, p53, and BRCA1, and the fact that both BRCA1 or TP53 mutations are involved in breast cancer tumorigenesis, we undertook the characterization of the entire coding sequence, intron/exon boundaries, and p53- and ZNF350-binding sequences of this potential breast cancer susceptibility candidate gene in a sample set of 96 women affected with breast cancer from non-BRCA1 and BRCA2 French Canadian families with a high risk of breast cancer and 95 healthy controls from the same population. Although none of the 12 identified sequence variations show a significant difference in frequency between both sample sets, haplotype phasing and frequency estimations identified a common haplotype displaying a higher frequency among the control group. As the variants present on this particular haplotype are noncoding variants in either intron 2 or 3, this finding will have to be further investigated in larger cohorts and other populations. In this regard, our study also identified tagging single nucleotide polymorphisms (tSNPs), providing useful data for other large-scale association studies.
Desjardins S, Belleau P, Labrie Y, et al.Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.
Int J Cancer. 2008; 122(1):108-16 [PubMed
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Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45. Direct sequencing of ZBRK1 entire coding region in affected breast cancer individuals from 97 high-risk French Canadian breast/ovarian cancer families and 94 healthy controls led to the identification of 18 genomic variants. Haplotype analyses, using PHASE, COCAPHASE and HaploStats programs, put in evidence 3 specific haplotypes which could potentially modulate breast cancer risk, and among which 2 that are associated with a potential protective effect (p = 0.01135 and p = 0.00268), while another haplotype is over-represented in the case group (p = 0.00143). Further analyses of these haplotypes indicated that a strong component of the observed difference between both groups emerge from the first 5 variants (out of 12 used for haplotype determination). The present study also permitted to determine a set of tagging SNPs that could be useful for subsequent analyses in large scale association studies. Additional studies in large cohorts and other populations will however be needed to further evaluate if common and/or rare ZBRK1 sequence variants and haplotypes could be associated with a modest/intermediate breast cancer risk.
Figueroa JD, Malats N, Rothman N, et al.Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk.
Carcinogenesis. 2007; 28(8):1788-93 [PubMed
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The double-strand break DNA repair (DSBR) pathway is implicated in maintaining genomic stability and therefore could affect bladder cancer risk. Here we present data evaluating 39 single-nucleotide polymorphisms (SNPs) in seven candidate genes whose products are involved in DNA break sensing (NBS1, BRCA1 interacting genes BRIP1 and ZNF350), non-homologous end-joining (NHEJ) DNA repair (XRCC4) and homologous recombination (HR) repair (RAD51, XRCC2 and XRCC3). SNPs for RAD51 and XRCC2 covered most of the common variation. Associations with bladder cancer risk were evaluated in 1,150 newly diagnosed cases of urinary bladder transitional cell carcinomas and 1,149 controls conducted in Spain during 1997-2001. We found that the genetic variants evaluated significantly contributed to bladder cancer risk (global likelihood ratio test P = 0.01). Subjects with the ZNF350 R501S (rs2,278,415) variant allele showed significantly reduced risk compared with common homozygote variants, odds ratio (OR) [95% confidence interval (95% CI)]: 0.76 (0.62-0.93) per variant allele. Carriers of a putative functional SNP in intron 7 of XRCC4 (rs1,805,377) had significantly increased bladder cancer risk compared with common homozygotes: 1.33 (1.08-1.64) per variant allele. Lastly, XRCC2 homozygote variants for three promoter SNPs (rs10,234,749, rs6,464,268, rs3,218,373) and one non-synonymous SNP (rs3,218,536, R188H) were associated with reduced bladder cancer risk (ORs ranging from 0.36 to 0.50 compared with common homozygotes). Meta-analysis for XRCC3 T241M (rs861,539) had a significant small increase in risk among homozygote variants: OR (95% CI) = 1.17 (1.00-1.36). Results from this study provide evidence for associations between variants in genes in the DSBR pathway and bladder cancers risk that warrant replication in other study populations.
Lee YK, Thomas SN, Yang AJ, Ann DKDoxorubicin down-regulates Kruppel-associated box domain-associated protein 1 sumoylation that relieves its transcription repression on p21WAF1/CIP1 in breast cancer MCF-7 cells.
J Biol Chem. 2007; 282(3):1595-606 [PubMed
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The role of post-translational modification, such as sumoylation, in modulating the efficacy of doxorubicin (Dox) treatment remains unclear. Transcriptional cofactor KRAB domain-associated protein 1 (KAP1) has been shown to complex with the KRAB zinc finger protein, ZBRK1, to repress the transcription of target genes. Through a combination of proteomic screening and site-directed mutagenesis approaches, we have identified lysines 554, 779, and 804 as the major sumoylation sites in KAP1. We then present evidence that Dox-mediated induction of cell cycle regulator p21 expression is differentially regulated by KAP1 sumoylation status. Moreover, the KAP1 sumoylation level was transiently decreased upon Dox exposure, and transfection with the KAP1 sumoylation mimetic, SUMO-1-KAP1, desensitizes breast cancer MCF-7 cells to Dox-elicited cell death. The sumoylation-dependent stimulation of KAP1 function is achieved by enhancing the methylation of H3-K9 and attenuating the acetylation of H3-K9 and H3-K14 at the p21 core promoter. We also show that occupancy of ZBRK1 response elements located at the p21 promoter by ZBRK1.KAP1 is independent of KAP1 sumoylation. Hence, sumoylation of KAP1 represses p21 transcription via a chromatin-silencing process without affecting interaction between KAP1.ZBRK1 and DNA, thus providing a novel mechanistic basis for the understanding of Dox-induced de-repression of p21 transcription. Taken together, our results suggest that Dox-induced decrease in KAP1 sumoylation is essential for Dox to induce p21 expression and subsequent cell growth inhibition in MCF-7 cells.
Furuta S, Wang JM, Wei S, et al.Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature.
Cancer Cell. 2006; 10(1):13-24 [PubMed
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BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.
Silva FP, Hamamoto R, Furukawa Y, Nakamura YTIPUH1 encodes a novel KRAB zinc-finger protein highly expressed in human hepatocellular carcinomas.
Oncogene. 2006; 25(36):5063-70 [PubMed
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To achieve a better understanding of mechanisms that underlie hepatocarcinogenesis and to identify novel target molecules for diagnosis and therapy of hepatocellular carcinoma (HCC), we previously analysed gene-expression profiles of 20 HCC tissues on a cDNA microarray. Among the genes upregulated in the tumor tissues compared with their nontumor counterparts, we focused on a novel gene termed transcription-involved protein upregulated in HCC (TIPUH1) that putatively encoded a 500-amino-acid protein containing 12 zinc-finger domains and a Kruppel-associated box domain. Multiple-tissue northern blot analysis revealed it's testis- and placenta-specific expression in normal tissues. Colony-formation assay in soft agar showed that TIPUH1 conferred anchorage-independent growth to NIH3T3 cells, suggesting its oncogenic activity. Conversely, specific siRNA for TIPUH1 knocked down its expression in HCC cells, which resulted in their growth inhibition. We identified four TIPUH1-interacting proteins including TIF1beta, a transcription-intermediary protein, and three involved in pre-mRNA processing (hnRNPU, hnRNPF, and Nucleolin), suggesting that overexpressed TIPUH1 may play a role in hepatocarcinogenesis by regulating transcription and/or RNA processing of growth control genes. These data may contribute to a better understanding of liver neoplasia, and to the development of novel strategy for treatment of HCCs.
García-Closas M, Egan KM, Newcomb PA, et al.Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses.
Hum Genet. 2006; 119(4):376-88 [PubMed
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The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04-1.34) and 0.85 (0.73-0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05-1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04-1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10-1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59-1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene-gene interactions or associations in population subgroups will require even larger sample sizes.
Garcia V, García JM, Peña C, et al.The GADD45, ZBRK1 and BRCA1 pathway: quantitative analysis of mRNA expression in colon carcinomas.
J Pathol. 2005; 206(1):92-9 [PubMed
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GADD45 is a growth arrest-associated gene that is induced in response to DNA damage. This gene is a target for coordinate regulation by both ZBRK1 and BRCA1. A sequence within intron 3 of GADD45 supports specific assembly of the ZBRK1/BRCA1 complex. In this study, the relationships between GADD45, ZBRK1, and BRCA1 expression were investigated in colon carcinomas. mRNA expression of these three genes was analysed in 116 colon carcinomas by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Genetic and epigenetic changes that could alter expression of these genes were studied. Possible relationships between expression levels of GADD45, ZBRK1, and BRCA1, and a series of clinicopathological parameters classically associated with poor prognosis, were also examined. ZBRK1 showed a tendency towards underexpression, while GADD45 and BRCA1 were generally overexpressed. A direct relationship between these three genes was observed, with the exception of BRCA1 expression levels, similar to normal tissues, which showed a tendency to be associated with low levels of GADD45 mRNA. Concomitantly altered expression of ZBRK1 and BRCA1 was associated with GADD45 mRNA expression. Promoter hypermethylation was not observed in GADD45 or BRCA1, and no mutations in GADD45 or ZBRK1 were found in regions involved in the interaction between the GADD45 gene and the ZBRK1 and BRCA1 proteins. No clinicopathological parameter was correlated with altered GADD45 or ZBRK1 expression but there was a statistically significant relationship between BRCA1 levels and the sex of patients. In conclusion, these results suggest that this pathway, involved in the response to DNA damage, is deregulated in colon carcinomas, and concomitantly altered expression of ZBRK1 and BRCA1 has an additive effect on GADD45 regulation. This is the first study in human carcinomas to analyse the relationships between expression of GADD45, ZBRK1, and BRCA1 mRNA.
Sigurdson AJ, Hauptmann M, Chatterjee N, et al.Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes.
BMC Cancer. 2004; 4:9 [PubMed
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BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFss1, IGFBP3) were evaluated.
METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported.
RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3-3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1-3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6-29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFss1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P.
CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted.
Garcia V, Domínguez G, García JM, et al.Altered expression of the ZBRK1 gene in human breast carcinomas.
J Pathol. 2004; 202(2):224-32 [PubMed
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The ZBRK1 protein is a member of the KRAB-ZFP family. It functions as a transcriptional repressor by binding to its recognition sequence within target genes and producing a nucleoprotein complex containing its co-repressor BRCA1 and also probably the co-repressor KAP-1. Alterations that affect the ZBRK1 gene have not been reported in human tumours. For this reason, possible alterations in the ZBRK1 gene have been studied by analysing mRNA expression using real-time polymerase chain reaction (PCR), and gene sequence using single strand conformation polymorphism (SSCP) analysis and DNA sequencing, in 61 patients with primary breast carcinomas. BRCA1 mRNA expression and allelic loss were also studied in 25 of the same patients. ZBRK1 was underexpressed in 28 (45.9%) and overexpressed in 18 (29.5%) of the 61 cases. No significant association was observed between ZBRK1 mRNA expression and clinicopathological parameters. Loss of heterozygosity of the BRCA1 gene was found in 3 of 23 (13%) informative cases and BRCA1 mRNA expression was altered in 11 of 25 (44%) cases. No significant correlation was found between altered BRCA1 expression and the different types of ZBRK1 mRNA expression. Nine polymorphisms were found in the ZBRK1 sequence, with no significant differences between patients and control subjects. Altered ZBRK1 expression correlated significantly with two of these polymorphisms. A point mutation in one polymorphism and allelic loss in one patient were also observed, findings that indicate that these inactivation mechanisms do not frequently affect this gene. Altered expression of the ZBRK1 gene is therefore frequent in primary breast carcinoma. The functional significance of the polymorphisms in this gene is unclear.
Rutter JL, Smith AM, Dávila MR, et al.Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals.
Hum Mutat. 2003; 22(2):121-8 [PubMed
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Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high-risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Hum Mutat 22:121-128, 2003. Published 2003 Wiley-Liss, Inc.