An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer

Weichselbaum, Ralph R.; Ishwaran, Hemant; Yoon, Taewon; Nuyten, Dimitry S.A.; Baker, Samuel White; Khodarev, Nikolai N.; Su, Andy; Shaikh, Arif; Roach, Paul D.; Kreike, Bas; Roizman, Bernard; Bergh, Jonas; Pawitan, Yudi; Vijver, Marc J. van de; Minn, Andy J.

doi:10.1073/pnas.0809242105

Cited by 498 publications

(576 citation statements)

References 17 publications

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“…Using the same approaches, we found that activation of a STAT1-dependent pathway mediates resistance to radiation treatment and predicts response to adjuvant chemotherapy and radiation in breast cancer patients (30)(31)(32). Thus, these approaches have allowed the identification of biologically relevant and differentially expressed pathways in experimental models.…”

Section: Discussionmentioning

confidence: 94%

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

Pitroda

Khodarev

Beckett

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in human breast cancers. Although MUC1 modulates the activity of estrogen receptor ␣ (ER), there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for breast cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of genes involved in cholesterol and fatty acid metabolism. A 38-gene set of experimentally derived MUC1-induced genes associated with lipid metabolism was applied to the analysis of ER ؉ breast cancer patients treated with tamoxifen. The results obtained from 2 independent databases demonstrate that patients overexpressing MUC1 and the lipid metabolic pathways are at significantly higher risk for death and recurrence/distant metastasis. By contrast, these genes were not predictive in untreated patients. Furthermore, a positive correlation was found between expression of the 38-gene set and the ER signaling pathway. These findings indicate that (i) MUC1 regulates cholesterol and fatty acid metabolism, and (ii) activation of these pathways in ER ؉ breast cancers predicts failure to tamoxifen treatment.breast cancer ͉ expression profiling ͉ lipid metabolism ͉ cholesterol biosynthesis ͉ risk factors

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Section: Discussionmentioning

confidence: 94%

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

Pitroda

Khodarev

Beckett

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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100

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“…IFN-related DNA damage resistance signature (+) xenografts were more resistant to doxorubicin chemotherapy compared with IFN-related DNA damage resistance signature (−) tumors (45). Moreover, a signature of IFN-related genes was associated with prediction of resistance across cell lines and primary tumors of different cancer types and was associated with a clinically adverse outcome after radiotherapy and chemotherapy for breast carcinoma (45). This signature of an IFN-induced pathway correlated with resistance to 5-AZA-dC and HDAC inhibitor induced DNA damage in SCLC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have identified a strong correlation between the constitutive expression of ISGs, and radiotherapy and chemotherapy resistance (45). Constitutive high expression of IFN/STAT1-regulated genes protected tumor cells from the cytotoxic effect of cisplatin and fludarabine (46,47).…”

Section: Discussionmentioning

confidence: 99%

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Luszczek

Cheriyath

Mekhail

et al. 2010

Molecular Cancer Therapeutics

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Because epigenetic inhibitors can reduce cancer cell proliferation, we tested the hypothesis that concurrent inhibition of histone acetylation and DNA methylation could synergistically reduce the viability of small cell lung cancer (SCLC) cells. Sub-IC 50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine (5-AZA-dC) and the histone deacetylase (HDAC) inhibitors (LBH589 or MGCD0103) synergistically reduced the proliferation of five of nine SCLC cell lines. Loss of viability of sensitive SCLC cells did not correlate with the inhibition of either DNMT1 or HDACs, suggesting nonepigenetic mechanisms for synergy between these two classes of epigenetic modulators. Because combinations of 5-AZA-dC and HDAC inhibitors had marginal effects on the apoptosis index, Comet assay was undertaken to assess DNA damage. MGCD0103 and 5AZA-dC cotreatment augmented DNA damage in SCLC cells, resulting in increased tail length and moment in Comet assays by 24 hours in sensitive cell lines (P < 0.01). Consistent with augmented DNA damage, combination of a DNMT and HDAC inhibitor markedly increased the levels of phospho-H2A.X in sensitive cells but not in resistant ones. Comparison of basal gene expression between resistant and sensitive cells identified markedly higher basal expression of IFN-stimulated genes in the resistant cell lines, suggesting that IFN-stimulated gene expression may determine SCLC cell sensitivity to epigenetic modulators or other DNA damaging agents. Mol Cancer Ther; 9(8); 2309-21. ©2010 AACR.

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“…Furthermore, a potential involvement of the ISGylation system in oncogenesis and tumor progression has been documented by the dysregulated expression of ISGylation components in tumors of different histological origin Feng et al, 2008), which could be associated with a poor prognosis of patients (Bektas et al, 2008). In addition, an altered ISG15 regulation is correlated with susceptibility/ resistance to chemotherapeutics and radiation, suggesting that ISG15 can serve as a novel biomarker for drug sensitivity (Desai et al, 2008;Weichselbaum et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

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The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, ARdependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR þ androgensensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

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An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer

Cited by 498 publications

References 17 publications

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Expression, regulation and function of the ISGylation system in prostate cancer

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