Ceramide galactosyltransferase (UGT8) is a molecular marker of breast cancer malignancy and lung metastases

Dzięgiel, Piotr; Owczarek, Tomasz B.; Plaz̀uk, E; Gomułkiewicz, Agnieszka; Majchrzak, Michał; Podhorska-Okołów, Marzena; Driouch, Keltouma; Lidereau, Rosette; Ugorski, Maciej

doi:10.1038/sj.bjc.6605750

Cited by 57 publications

(49 citation statements)

References 46 publications

(60 reference statements)

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“…Reaction intensities with rabbit polyclonal antibodies for UGT8 were calculated on the basis of the semiquantitative IRS scale of Remmele and Stegner (1987) The question remains as to the biological meaning of increased expression of UGT8. This enzyme is involved in the biosynthesis of GalCer, and it is possible that in human cancer, including breast cancer, an accumulation of this glycosphingolipid in tumor cells inhibits apoptosis, which facilitates metastatic cells to survive in the hostile micro-environment of the target organ [15,19]. Breast tumors and canine mammary neoplasia have many features in common.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown recently that expression of UGT8 is highly elevated in breast cancer metastases to the lung in comparison to matched primary tumors and increased expression of this enzyme are associated with progression to a more malignant phenotype [12][13][14][15]. Based on these results we studied the expression of UGT8 in canine tubulopapillary carcinomas and simple adenomas.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the results obtained for human breast cancer (Dziegiel et al, 2010), the intensities of UGT8 staining in node-positive and node-negative tumors were also compared. Node-positive cases were characterized by a higher average IRS value (5.25 ± 1.91) than nodenegative cases (4.45 ± 2.09).…”

Section: Discussionmentioning

confidence: 99%

“…Studies performed on the level of mRNA expression using microarray analysis and quantitative RT-PCR were further confirmed by immunohistochemistry. It has been shown that high expression of UGT8 protein is a significant index of tumor aggressiveness and a potential marker for the prognostic evaluation of lung metastases in breast cancer [15]. So far, there were no reports about the expression of UGT8 in canine mammary gland tumors, therefore, the present study was undertaken to analyses the expression of this enzyme in malignant and benign canine tumors.…”

Section: Introductionmentioning

confidence: 99%

“…All tissue sections were counter-stained with Mayer's hematoxylin. As positive control for the UGT8 IHC a previously breast cancer specimen characterized by its high expression in cancer cells was utilized, whereas Primary Negative Control (Dako) was used as the negative control [15].…”

Section: Histopathological Examination and Immunohistochemical Reactimentioning

confidence: 99%

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Ceramide galactosyltransferase (UGT8) as a molecular marker of canine mammary tumor malignancy

Nowak

Dzięgiel

Madej

et al. 2013

Folia Histochem Cytobiol.

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Thirty-two canine mammary tubulopapillary carcinomas and 14 simple adenomas were studied by immunohistochemistry for the expression of UDP-galactose:ceramide galactosyltransferase (UGT8). The majority of tissue specimens (57%) representing adenomas had no or weak reaction with anti-UGT8 antibodies (0-2 pts according to IRS scale) in comparison to the majority of carcinomas (90%) which stained with high intensities (3-9 pts according to IRS scale). When the average values of the reaction intensities (IRS) for malignant and benign tumors were compared, using the Mann-Whitney U-test, significant differences in UGT8 expression between them were found (P < 0.001). Mammary tubulopapillary carcinomas were further analyzed by IHC and the same rabbit polyclonal antibody directed against UGT8 according to their malignancy grade. It was found that the level of UGT8 increased in tumor specimens together with their grading. A comparison of the average values of the reaction intensity (IRS scale) revealed a significant difference (Mann-Whitney U-test, P < 0.05) in UGT8 expression between tumors representing malignancy grades G3 and G1. Based on the obtained results, it is proposed that UGT8 is associated with malignancy of canine mammary gland cells and may have a potential value as a diagnostic marker.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Histopathological Examination and Immunohistochemical Reactimentioning

confidence: 99%

See 3 more Smart Citations

Ceramide galactosyltransferase (UGT8) as a molecular marker of canine mammary tumor malignancy

Nowak

Dzięgiel

Madej

et al. 2013

Folia Histochem Cytobiol.

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Substrate reduction therapy for Krabbe's disease

Sands

Levine

2016

J of Neuroscience Research

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Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose‐sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP‐galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand‐alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult‐onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.

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Quantitative analysis of the UDP‐glucuronosyltransferase transcriptome in human tissues

Zhou,

Montalvo,

Collins

et al. 2023

Pharmacology Res & Perspec

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UDP‐glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that play important roles in the detoxification of endogenous and exogenous substrates. The 22 human UGTs belong to four families (UGT1, UGT2, UGT3, and UGT8) and differ in their expression, substrate specificity, UDP‐sugar preference, and physiological functions. Differential expression/activity of the UGTs contributes to interperson variability in drug responses and toxicity, hormone homeostasis, and disease/cancer risks. However, in normal tissues, the tissue‐specific expression profiles and transcriptional regulation of the UGTs are still not fully understood. In this study, we comprehensively analyzed the transcriptome of 22 UGTs in 54 human tissues/regions using RNAseq data from GTEx. We then validated the findings in the liver and small intestine samples using real‐time PCR. Our results showed large interindividual variability across tissues in the expression of each UGT and the overall composition of UGT pools, consisting of different UGTs and their splice isoforms. Our results also revealed coexpression of the UGTs, Cytochrome P450s, and many transcription factors in the liver, suggesting potential coregulation or functional coordination. Our results provide the groundwork for future studies to detail further the regulation of the expression and activity of the UGTs.

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Ceramide galactosyltransferase (UGT8) is a molecular marker of breast cancer malignancy and lung metastases

Cited by 57 publications

References 46 publications

Ceramide galactosyltransferase (UGT8) as a molecular marker of canine mammary tumor malignancy

Ceramide galactosyltransferase (UGT8) as a molecular marker of canine mammary tumor malignancy

Substrate reduction therapy for Krabbe's disease

Quantitative analysis of the UDP‐glucuronosyltransferase transcriptome in human tissues

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