Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCA1 is implicated in cellular responses to DNA damage, thereby substantially contributing to maintenance of the genome integrity. Mutations in the BRCA1 gene occur in breast and ovarian cancer and mutations that disable p53 are frequently found in human cancers, often accompanied by mutations in additional genes, contributing to tumor progression or high-grade malignancy. Therefore, the role of BRCA1 in the sensitivity to anticancer agents in p53-deficient cells was investigated using p53-deficient mouse knockout cell lines either deficient or proficient in Brca1 function. We report that Brca1-deficiency in p53-null cells was associated with increased sensitivity to the topoisomerase I poisons camptothecin and topotecan, the topoisomerase II poisons doxorubicin, mitoxantrone and etoposide, and to the platinum compounds carboplatin and oxaliplatin, but not to the antimetabolites 5-fluorouracil and gemcitabine and the taxanes docetaxel and paclitaxel. The increased growth inhibition to doxorubicin after loss of Brca1 correlated with increased cell killing caused by increased apoptosis. The data presented here indicate that Brca1 modulates p53-independent DNA damage response pathways and they support the case of a role of Brca1 to protect cells from apoptosis-mediated cell death in p53-deficient cells. These results suggest a higher chemotherapy susceptibility of cells disabled in both functions and they foster the concept that functional inhibition of BRCA1 may be a valuable adjunct to anticancer agents to increase the efficacy of chemotherapy in the treatment of p53-mutated cancers.
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PMID:The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. 1268 87

Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.
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PMID:Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. 1272 61

Genomic instability is thought to underlie tumor progression in solid tumors, such as breast cancer. Although evidence that the hereditary breast cancer genes, BRCA1 and BRCA2, are involved in DNA repair suggests that genomic instability plays an important role in hereditary breast tumorigenesis, genomic instability remains poorly characterized in sporadic breast cancers. Using a DNA fingerprinting technique, inter-(simple sequence repeat) PCR (inter-SSR PCR), the degree of genomic instability was quantified in 47 sporadic breast cancers compared with matched adjacent normal breast tissues. Almost all sporadic breast cancers show significant genomic instability by inter-SSR PCR. The distribution of this instability is bimodal; 57% of the tumors show fewer changes, whereas 43% show striking genomic alterations. Further analysis of two inter-SSR PCR tumor-normal differences revealed a genomic amplification and probable deletion. Thus, inter-SSR PCR can detect chromosomal breakage-related genomic alterations in most sporadic breast cancers. Genomic instability as detected by inter-SSR PCR is not correlated with aneuploidy, suggesting that this technique preferentially detects intrachromosomal alterations. Chromosomal instability in breast cancer can therefore be subdivided into at least two groups: (a) intrachromosomal and (b) gross chromosomal. Allelic imbalance at markers at the 13q13 and retinoblastoma loci (13q) and not at 17q loci was significantly associated with high levels of intrachromosomal instability, suggesting genes at 13q13 and retinoblastoma loci are either selectively targeted or involved in the genesis of genomic instability in sporadic breast cancers.
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PMID:Widespread bimodal intrachromosomal genomic instability in sporadic breast cancers associated with 13q allelic imbalance. 1290 36

Sporadic cancers and familial breast cancers are characterized by an increase in genetic instability. Little is known about whether mismatch repair defects accompany this genetic instability. We investigated invasive and/or in situ breast cancers from 30 women with deleterious BRCA1/2 mutations and unclassified variant BRCA1/2 alterations. Forty cases of sporadic breast cancers were also investigated, including 7 medullary carcinomas. Malignant and benign lesions were examined from all cases to better understand tumor progression. Automated immunohistochemistry, with antibodies directed against hMLH1 and hMSH2, was used to screen cases for possible mismatch repair defects. When loss of expression was noted, DNA ploidy was performed by cytomorphometry. DNA, after laser microdissection, was extracted from a majority of familial cases and their corresponding controls, and microsatellite instability analysis was performed. None of the familial or sporadic cases had loss of hMSH2 expression. All but one lesion, a DCIS arising in a deleterious BRCA2 mutation carrier, had loss of hMLH1 expression and a tetraploid profile by image cytomorphometry. There was no MSI in any explored lesions (n = 34), as determined by molecular analysis, including the DCIS with loss of hMLH1 expression. We conclude that DNA mismatch repair defects involving hMLH1 and hMSH2 underexpression are extremely rare events in sporadic and familial breast cancer. Mismatch repair gene mutations may be secondary random events in breast cancer progression.
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PMID:Microsatellite instability in hereditary and sporadic breast cancers. 1452 Jun 95

Telomerase, an enzyme that maintains telomere length, plays major roles in cellular immortalization and cancer progression. We found that an exogenous BRCA1 gene strongly inhibited telomerase enzymatic activity in human prostate and breast cancer cell lines and caused telomere shortening in cell lines expressing wild-type BRCA1 (wtBRCA1) but not a tumor-associated mutant BRCA1 (T300G). wtBRCA1 inhibited the expression of the catalytic subunit (telomerase reverse transcriptase [TERT]) but had no effect on the expression of a subset of other components of the telomerase holoenzyme or on the expression of c-Myc, a transcriptional activator of TERT. However, endogenous BRCA1 associated and partially colocalized with c-Myc; exogenous wtBRCA1 strongly suppressed TERT promoter activity in various cell lines. The TERT inhibition was due, in part, to suppression of c-Myc E-box-mediated transcriptional activity. Suppression of TERT promoter and c-Myc activity required the amino terminus of BRCA1 but not the carboxyl terminus. Finally, endogenous BRCA1 and c-Myc were detected on transfected mouse and human TERT promoter segments in vivo. We postulate that inhibition of telomerase may contribute to the BRCA1 tumor suppressor activity.
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PMID:BRCA1 inhibition of telomerase activity in cultured cells. 1461 9

Mutations within the BRCA1 tumor suppressor gene occur frequently in familial epithelial ovarian carcinomas but they are a rare event in the much more prevalent sporadic form of the disease. However, decreased BRCA1 expression occurs frequently in sporadic tumors, and the magnitude of this decrease has been correlated with increased disease progression. The near absence of somatic mutations consequently suggests that there are alternative mechanisms that may contribute to the observed loss of BRCA1 in sporadic tumors. Indeed, both allelic loss at the BRCA1 locus and epigenetic hypermethylation of the BRCA1 promoter play an important role in BRCA1 down-regulation; yet these mechanisms alone or in combination do not always account for the reduced BRCA1 expression. Alternatively, misregulation of specific upstream factors that control BRCA1 transcription may be a crucial means by which BRCA1 is lost. Therefore, determining how regulators of BRCA1 expression may be co-opted during sporadic ovarian tumorigenesis will lead to a better understanding of ovarian cancer etiology and it may help foster the future development of novel therapeutic strategies aimed at halting ovarian tumor progression.
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PMID:The role of the breast cancer susceptibility gene 1 (BRCA1) in sporadic epithelial ovarian cancer. 1461 51

From the time of DNA replication until anaphase onset, sister chromatids remain tightly paired along their length. Ctf7p/Eco1p is essential to establish sister-chromatid pairing during S-phase and associates with DNA replication components. DNA helicases precede the DNA replication fork and thus will first encounter chromatin sites destined for cohesion. In this study, I provide the first evidence that a DNA helicase is required for proper sister-chromatid cohesion. Characterizations of chl1 mutant cells reveal that CHL1 interacts genetically with both CTF7/ECO1 and CTF18/CHL12, two genes that function in sister-chromatid cohesion. Consistent with genetic interactions, Chl1p physically associates with Ctf7p/Eco1p both in vivo and in vitro. Finally, a functional assay reveals that Chl1p is critical for sister-chromatid cohesion. Within the budding yeast genome, Chl1p exhibits the highest degree of sequence similarity to human CHL1 isoforms and BACH1. Previous studies revealed that human CHLR1 exhibits DNA helicase-like activities and that BACH1 is a helicase-like protein that associates with the tumor suppressor BRCA1 to maintain genome integrity. Our findings document a novel role for Chl1p in sister-chromatid cohesion and provide new insights into the possible mechanisms through which DNA helicases may contribute to cancer progression when mutated.
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PMID:Chl1p, a DNA helicase-like protein in budding yeast, functions in sister-chromatid cohesion. 1502 Apr 4

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2-related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations.
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PMID:ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers. 1554 18

Recent genomewide analyses of alternative splicing (AS) indicate that up to 70% of human genes may have alternative splice forms, suggesting that AS together with various posttranslational modifications plays a major role in the production of proteome complexity. Splice-site selection under normal physiological conditions is regulated in the developmental stage in a tissue type-specific manner by changing the concentrations and the activity of splicing regulatory proteins. Whereas spliceosomal errors resulting in the production of aberrant transcripts rarely occur in normal cells, they seem to be an intrinsic property of cancer cells. Changes in splice-site selection have been observed in various types of cancer and may affect genes implicated in tumor progression (for example, CD44, MDM2, and FHIT) and in susceptibility to cancer (for example, BRCA1 and APC). Splicing defects can arise from inherited or somatic mutations in cis-acting regulatory elements (splice donor, acceptor and branch sites, and exonic and intronic splicing enhancers and silencers) or variations in the composition, concentration, localization, and activity of regulatory proteins. This may lead to altered efficiency of splice-site recognition, resulting in overexpression or down-regulation of certain splice variants, a switch in splice-site usage, or failure to recognize splice sites correctly, resulting in cancer-specific splice forms. At least in some cases, changes in splicing have been shown to play a functionally significant role in tumorigenesis, either by inactivating tumor suppressors or by gain of function of proteins promoting tumor development. Moreover, cancer-specific splicing events may generate novel epitopes that can be recognized by the host's immune system as cancer specific and may serve as targets for immunotherapy. Thus, the identification of cancer-specific splice forms provides a novel source for the discovery of diagnostic or prognostic biomarkers and tumor antigens suitable as targets for therapeutic intervention.
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PMID:Alterations of pre-mRNA splicing in cancer. 1564 50

BRCA1, a breast and ovarian tumor suppressor, is a phosphoprotein whose cellular expression level is regulated in a cell cycle-dependent manner. BRCA1 interacts with BARD1 to generate significant ubiquitin ligase activity which catalyzes nontraditional Lys-6-linked polyubiquitin chains. However, it is not clear how the activity is regulated and how this affects BRCA1's multiple cellular functions. Here we show that the ubiquitin ligase activity of BRCA1-BARD1 is down-regulated by CDK2. During the cell cycle, BARD1 expression can largely be categorized into three patterns: moderately expressed in a predominantly unphosphorylated form in early G(1) phase, expressed at low levels in both phosphorylated and unphosphorylated forms during late G(1) and S phases, and highly expressed in its phosphorylated form during mitosis coinciding with BRCA1 expression. CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH(2) terminus in vivo and in vitro. Intriguingly, the BRCA1-BARD1-mediated in vivo ubiquitination of nucleophosmin/B23 (NPM) and autoubiquitination of BRCA1 are dramatically disrupted by coexpression of CDK2-cyclin A1/E1, but not by CDK1-cyclin B1. The inhibition of ubiquitin ligase activity is not due to the direct effect of the kinases on BARD1 because an unphosphorylatable mutant of BARD1, S148A/S251A/S288A/T299A, is still inhibited by CDK2-cyclin E1. Alternatively, BRCA1 and BARD1 are likely exported to the cytoplasm and their expressions are remarkably reduced by CDK2-cyclin E1 coexpression. Recognizing the importance of cyclin E1 overexpression in breast cancer development, these results suggest a CDK2-BRCA1-NPM pathway that coordinately functions in cell growth and tumor progression pathways.
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PMID:Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. 1566 73


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