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)

This subject was particularly important to discuss in the presence of Werner Kalow, 77 years young, who is considered as one of the grandfathers of this unique combination of medical research fields. It has become increasingly appreciated that dozens of human drug metabolism polymorphisms exist. The interindividual variabilities in drug metabolism discussed at this symposium do not represent small differences such as 50% or 3-fold but, rather, represent 10- to greater than 1000-fold differences. When attributed to a single gene, dramatic differences can be seen among family members, just as blue and brown eyes can occur in siblings. These differences can result in acute drug toxicity. In addition, there are chronic effects: over one's lifetime, striking differences in the metabolism of drugs, occupationally hazardous chemicals, and other environmental pollutants can lead to interindividual differences in the buildup of DNA damage (e.g., mutations, chromosomal breaks, rearrangements) leading to toxicity and tumor initiation, as well as leading to a buildup in nongenotoxic signals (signal transduction pathways without DNA damage) important for toxicity, tumor promotion, and tumor progression. The human UDP glucuronosyltransferase (UGT superfamily is known to comprise more than 10 genes in humans, and probably in other mammalian species. Breakthroughs in UGT gene mutations responsible for the Crigler-Najjar syndrome and Gilbert's disease have recently been reported. The human cytochrome P450 termed CYP3A4 is a major P450 enzyme in the liver and gastrointestinal tract, and the full impact of the CYP3A4 polymorphism has yet to be fully appreciated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacogenetics in clinical pharmacology and toxicology. 764 12

Breast cancer is considered to display a high degree of intratumor heterogeneity, without any obvious morphological and pathological steps to define sequential evolution, and its progression may vary among individual tumors. In an attempt to elucidate these etiological and phenotypic complexities, the present study, based on the fundamental concept that genomic instability is the engine of both tumor progression and tumor heterogeneity, was conducted to test the hypothesis that breast cancer pathogenesis is driven by double-strand break (DSB)-initiated chromosome instability (CIN). The rationale underlying this hypothesis is derived from the clues provided by family breast cancer syndromes, in which susceptibility genes, including p53, ATM, BRCA1 and BRCA2, are involved within the common functional pathway of DSB-related checkpoint/ repair. Because genomic deletion caused by DSB is reflected in the genetic mechanism of loss of heterozygosity (LOH), this genome-wide LOH study was conducted, using 100 tumors and 400 microsatellite markers. To minimize the effect of heterogeneity within tumors, the experimental technique of laser capture microdissection was used to ensure that genetic and phenotypic examinations were based on the same tumor cells. Support for our hypothesis comes from the observations that: (a) the extent of DSB-initiated CIN in tumors significantly increased as tumors progressed to poorer grades or later stages; (b) in the sequential steps toward CIN, the loci of p53 and ATM, the key checkpoint genes against DSB, were lost at the earliest stage; and (c) many loci identified to be important in breast tumorigenesis were the genomic sites possibly harboring the genes involved in DSB-related checkpoint/repair (including RAD51, RAD52, and BRCA1) or CIN (including FA-A, FA-D, and WRN), and a higher number of these loci showing LOH was significantly associated with increased level of DSB-initiated CIN (P < 0.0001). Breast cancers are thus considered to be sequentially progressive with CIN. However, CIN might also cause genetic heterogeneity, which was revealed by the findings that LOH at some markers was observed only in the component of ductal carcinoma in situ but not in the invasive component of the same tumors. In addition, some markers were found to preferentially lose at specific tumor grades, implying their contribution to genetic heterogeneity during tumor development. Therefore, this study suggests that breast cancer progression is clonal with regard to CIN, but different breast cancers would present distinct molecular profiles resulting from genetic heterogeneity caused by CIN.
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PMID:Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. 1091 64

Werner syndrome is a hereditary disorder characterized by the early onset of age-related symptoms, including cancer. The absence of a p53-WRN helicase interaction may disrupt the signal to direct S-phase cells into apoptosis for programmed cell death and contribute to the pronounced genomic instability and cancer predisposition in Werner syndrome cells. Results from coimmunoprecipitation studies indicate that WRN is associated with replication protein A (RPA) and p53 in vivo before and after treatment with the replication inhibitor hydroxyurea or gamma-irradiation that introduces DNA strand breaks. Analysis of the protein interactions among purified recombinant WRN, RPA, and p53 proteins indicate that all three protein pairs bind with similar affinity in the low nanomolar range. In vitro studies show that p53 inhibits RPA-stimulated WRN helicase activity on an 849-bp M13 partial duplex substrate. p53 also inhibited WRN unwinding of a short (19-bp) forked duplex substrate in the absence of RPA. WRN unwinding of the forked duplex substrate was specific, because helicase inhibition mediated by p53 was retained in the presence of excess competitor DNA and was significantly reduced or absent in helicase reactions catalyzed by a WRN helicase domain fragment lacking the p53 binding site or the human RECQ1 DNA helicase, respectively. p53 effectively inhibited WRN helicase activity on model DNA substrate intermediates of replication/repair, a 5' ssDNA flap structure and a synthetic replication fork. Regulation of WRN helicase activity by p53 is likely to play an important role in genomic integrity surveillance, a vital function in the prevention of tumor progression.
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PMID:p53 modulates RPA-dependent and RPA-independent WRN helicase activity. 1573 6

Oncogene-induced replication stress is recognized as the primary cause of accumulation of DNA damage and genome instability in precancerous cells. Although the molecular mechanisms responding to such type of replication perturbation are not fully characterized, it has been speculated that their dysfunction may enhance genome instability and accelerate tumor progression. Here, we show that the WRN protein, a member of the human RecQ helicases, is necessary to sustain replication fork progression in response to oncogene-induced replication stress. Loss of WRN affects cell cycle progression and results in enhanced accumulation of double-strand breaks and instability at common fragile sites in cells experiencing oncogene-induced replication stress. Moreover, we demonstrate that double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death. Overall, our findings give insights into the mechanisms protecting replication forks in cells experiencing oncogene-induced replication stress, and identify factors that, when mutated or dysfunctional, may enhance genome instability in precancerous cells. In addition, because concomitant depletion of WRN and MUS81 causes synthetic sickness in cells growing under oncogene-induced replication stress, our results support the possibility of targeting cancer cells with an impaired replication fork recovery pathway by a specific inactivation of the other parallel pathway.
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PMID:The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation. 2241 Jul 76

Oral squamous cell carcinoma (OSCC) constitutes over 90% of all cancers in the oral cavity. The prognosis for patients with invasive OSCC is poor; therefore, it is important to understand the molecular mechanisms of invasion and subsequent metastasis not only to prevent cancer progression but also to detect new therapeutic targets against OSCC. Recently, extracellular vesicles-particularly exosomes-have been recognized as intercellular communicators in the tumor microenvironment. As exosomic cargo, deregulated microRNAs (miRNAs) can shape the surrounding microenvironment in a cancer-dependent manner. Previous studies have shown inconsistent results regarding miR-200c-3p expression levels in OSCC cell lines, tissues, or serum-likely because of the heterogeneous characters of the specimen materials. For this reason, single-cell clone analyses are necessary to effectively assess the role of exosome-derived miRNAs on cells within the tumor microenvironment. The present study utilized integrated microarray profiling to compare exosome-derived miRNA and exosome-treated cell-derived mRNA expression. Data were acquired from noninvasive SQUU-A and highly invasive SQUU-B tongue cancer cell clones derived from a single patient to determine candidate miRNAs that promote OSCC invasion. Matrigel invasion assays confirmed that hsa-miR-200c-3p was a key pro-invasion factor among six miRNA candidates. Consistently, silencing of the miR-200c-3p targets, CHD9 and WRN, significantly accelerated the invasive potential of SQUU-A cells. Thus, our data indicate that miR-200c-3p in exosomes derived from a highly invasive OSCC line can induce a similar phenotype in non-invasive counterparts.
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PMID:miR-200c-3p spreads invasive capacity in human oral squamous cell carcinoma microenvironment. 2898 Nov 69

Maintenance of genome stability is essential to prevent the accumulation of DNA mutations that can initiate oncogenesis and facilitate tumor progression. Studies of DNA repair genes have revealed a highly dynamic and redundant network of genes and proteins responsible for maintaining genome stability. Cancer cells are often deficient in DNA repair, and the resulting genome instability decreases their fitness but also allows for more rapid evolution under selective pressure. Of particular interest for genome stability are the RecQ class of helicases. Five genes in this class, RECQL1, BLM, WRN, RECQL4, and RECQL5, are unique to mammals, as simpler eukaryotes and bacteria appear to have only one homolog, RecQ. The precise role of each of the five mammalian RecQ helicases remains to be determined. Whereas loss of function mutations of BLM, WRN, and RECQL4 in humans are associated with specific diseases, RECQL1 and RECQL5 have not yet been associated with specific disorders. Mice deficient in Recql5 are more likely to develop cancer, and human cells deficient in RECQL5 display chromosomal instability and elevated sister chromatid exchange events, similar to cells deficient in any of the other RecQ helicases. Recent studies support the hypothesis that RECQL5 can resolve intermediate DNA repair structures resulting from the collision of DNA transcription and replication machinery. In this review, we aim to summarize current knowledge regarding RECQL5 in the context of DNA repair, replication, and transcription to help uncover the role of RECQL5 in the maintenance of genome stability.
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PMID:RECQL5 at the Intersection of Replication and Transcription. 3252 48