Circulating tumoral cells lack circadian-rhythm in hospitalized metastasic breast cancer patients

Martín, Miguel; Maestro, M.L.; Vidaurreta, Marta; Veganzones, Silvia; Villalobos, L.; Rodríguez-Lajusticia, Laura; Rafael, Sara; Casla, María Teresa Sanz; Casado, Antonio; Sastre, Javier; Arroyo, Manuel; Dı́az-Rubio, Eduardo

doi:10.1007/s12094-006-0139-0

Cited by 6 publications

(6 citation statements)

References 34 publications

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“…After single exposure, NGTX carcinogens induced changes in the expression of the following pathways: circadian rhythm; PPAR signaling; fatty acid metabolism; metabolism of xenobiotics by cytochrome p450; and glycine, serine and threonine metabolism. The circadian rhythm pathway is involved in biological rhythms; and previous studies have found that when these rhythms are disrupted, melatonin (a hormone that inhibits the occurrence of tumors) decreases, while the occurrence of cancer increases30. Moreover, a recent study showed that in normal organisms, circadian rhythms and the cell cycle are strongly connected, as the cell cycle is under the control of circadian rhythms.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis

Lee

Yum

Kim

et al. 2013

Sci Rep

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A rapid and sensitive method to determine the characteristics of carcinogens is needed. In this study, we used a microarray-based genomics approach, with a short-term in vivo model, in combination with insights from statistical and mechanistic analyses to determine the characteristics of carcinogens. Carcinogens were evaluated based on the different mechanisms involved in the responses to genotoxic carcinogens and non-genotoxic carcinogens. Gene profiling was performed at two time points after treatment with six training and four test carcinogens. We mapped the DEG (differentially expressed gene)-related pathways to analyze cellular processes, and we discovered significant mechanisms that involve critical cellular components. Classification results were further supported by Comet and Micronucleus assays. Mechanistic studies based on gene expression profiling enhanced our understanding of the characteristics of different carcinogens. Moreover, the efficiency of this study was demonstrated by the short-term nature of the animal experiments that were conducted.C arcinogens can be categorized as either genotoxic (GTX) or non-genotoxic (NGTX), according to their specific pathogenic mechanism. Most GTX carcinogens are electrophiles that interact directly with DNA through the formation of covalent bonds, resulting in DNA-carcinogen complexes (DNA adducts). These complexes lead to various types of DNA damage, including the formation of cross-links between the two helices, chemical bonds between adjacent bases, removal of DNA bases (hydration) and cleavage of the DNA strands, all of which result in modifications to the information stored within the DNA. Such mutations are typically fixed by DNA repair mechanisms; however, if DNA replication occurs prior to the action of a repair mechanism, mutations can become permanent and may eventually cause tumors. Conversely, NGTX carcinogens have no direct interaction with DNA; they are believed to cause tumors by disrupting cellular structures and by changing the rate of either cell proliferation or of processes that increase the risk of genetic error.These types of differences in the sub-mechanisms of carcinogenicity also affect the gene expression patterns of cells exposed to carcinogens, which encourages genomic approaches in toxicological studies [1][2][3] . Previous studies have found that GTX carcinogens activate p53 tumor suppressor gene products in response to DNA damage, which leads to the initiation of sub-mechanisms, including the activation of cell cycle arrest, apoptosis and DNA repair processes, and which results in changes in the expression of specific genes, such as Cdkn1a, Mdm2 and Bcl2 4,5 . NGTX carcinogens display complicated and varying mechanisms that are not completely understood. However, these mechanisms have been associated with an alteration in oxidative stress, modulation of metabolizing enzymes, induction of peroxisome proliferation, alteration of intercellular communication and disruption of the balance between proliferation and apoptosis 5,6 . Theref...

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Section: Discussionmentioning

confidence: 99%

Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis

Lee

Yum

Kim

et al. 2013

Sci Rep

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“…Recently, Tokunaga et al showed that there was no relationship between tumor removal time and the expression level of circadian genes in ovarian tumor [18]. Furthermore, it has been determined that circulating breast tumor cells have no circadian rhythm [27]. As such, adjacent individual tumor cells may be in various stages of the circadian phase, and it is therefore appropriate to compare expression levels between patients, as any sample of tumor cells should represent the average expression for a given individual over all stages.…”

Section: Discussionmentioning

confidence: 99%

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer

Longrais

et al. 2009

Breast Cancer Res Treat

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Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21–0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19–0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96–3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (χ2 (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.

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“…If all dividing cells are entrained the same way to the circadian rhythm, then attaining an optimum balance is more complicated. However, some evidence is available that at least in some cases, cancer cells have altered organization of the cell cycle relative to the circadian rhythm (Canaple et al, 2003;Garcia-Saenz et al, 2006). To the degree that this is true, then knowledge of the circadian expression of drug targets in normal cells may provide a basis for reducing toxicity.…”

Section: Discussionmentioning

confidence: 99%

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

Almon

Yang

Lai³

et al. 2008

J Pharmacol Exp Ther

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Chronopharmacology is an important but under-explored aspect of therapeutics. Rhythmic variations in biological processes can influence drug action, including pharmacodynamic responses, due to circadian variations in the availability or functioning of drug targets. We hypothesized that global gene expression analysis can be useful in the identification of circadian-regulated genes involved in drug action. Circadian variations in gene expression in rat liver were explored using Affymetrix gene arrays. A rich time series involving animals analyzed at 18 time points within the 24-h cycle was generated. Of the more than 15,000 probe sets on these arrays, 265 exhibited oscillations with a 24-h frequency. Cluster analysis yielded five distinct circadian clusters, with approximately two thirds of the transcripts reaching maximal expression during the dark/active period of the animal. Of the 265 probe sets, 107 were identified as having potential therapeutic importance. The expression levels of clock genes were also investigated in this study. Five clock genes exhibited circadian variation in the liver, and data suggest that these genes may also be regulated by corticosteroids.

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Circulating tumoral cells lack circadian-rhythm in hospitalized metastasic breast cancer patients

Abstract: No-differences between daytime and night-time CTC were observed. Therefore, we could not ascertain CTC circadian-rhythm in hospitalized metastasic breast cancer patients.

Cited by 6 publications

References 34 publications

Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis

Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

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