The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

Bektas, Nuran; Noetzel, Erik; Veeck, Jürgen; Press, Michael F.; Kristiansen, Glen; Naami, Amjad; Hartmann, Arndt; Dimmler, Arno; Beckmann, Matthias W.; Knüchel, Ruth; Fasching, Peter A.; Dahl, Edgar

doi:10.1186/bcr2117

Cited by 100 publications

(94 citation statements)

References 32 publications

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“…When compared with non-malignant tissues, ISG15 is upregulated in endometrial tumors (Desai et al, 2006), pancreatic adenocarcinomas (Iacobuzio-Donahue et al, 2003), breast cancer (Bektas et al, 2008) and in bladder cancer independent from inflammation . In some cases, this upregulation was associated with enhanced metastatic capacity as well as with poor patient prognosis (Bektas et al, 2008) In contrast, Ube1L is often lost or downregulated in lung cancer, indicating a tumorsuppressor function of Ube1L in this tissue (Pitterle et al, 1998). The EFP expression is increased in advanced breast tumors and positively correlates with a poor prognosis (Sakuma et al, 2005;Suzuki et al, 2005), which seems to be tightly connected to the specific function of EFP in the regulation of ER activity.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that ISGylation negatively regulates the ubiquitin-proteasome pathway by direct interference with polyubiquitination (Desai et al, 2006). 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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…STAT1 is known to regulate transcription of a large set of response genes when IFN signaling is engaged. Unexpectedly, oncogenic transformation by Ras was shown to induce the expression of IFN-responsive genes including Interferon Stimulated Gene 15 (ISG15) that is also linked to poor prognosis and increased cell migration (21)(22)(23). We investigated whether such a gene regulation profile could be reproduced ex vivo upon NeuNT transformation.…”

Section: Resultsmentioning

confidence: 99%

Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis

Laurin

Pelletier

et al. 2013

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

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Progression of solid tumors to the metastatic stage is accountable for the majority of cancer-related deaths. Further understanding of the molecular mechanisms governing metastasis is essential for the development of antimetastatic regimens. Here, we aimed to identify Rac activators that could promote metastasis downstream of human epithelial growth factor receptor 2 (HER2). We investigated if Dedicator of Cytokinesis 1 (DOCK1), based on its evolutionarily conserved role in receptor tyrosine kinases (RTKs)-mediated Rac activation and cell invasion, could be a regulator of metastasis. We report that high expression of DOCK1 in HER2 + and basal breast cancer subtypes inversely correlates with human patients' survival. Mechanistically, DOCK1 interacts with HER2 and promotes HER2-induced Rac activation and cell migration. To gain further insight, we developed a HER2 breast cancer mouse model with mammary-gland-specific inactivation of DOCK1. In this in vivo model, a significant decrease in tumor growth and metastasis in lungs was found in animals where DOCK1 is inactivated. Furthermore, we found that DOCK1 is required for maximal activation of two HER2 effectors, c-JUN and STAT3. Using an unbiased gene profiling approach, we identified a mammary tumor DOCK1-associated gene signature enriched for genes implicated in response to IFN type I. This analysis revealed a unique set of genes, including Receptor Transporter Protein 4 (RTP4) and STAT1, for which the expression levels can be used to independently predict breast cancer outcome in HER2 + patients. Our work demonstrates DOCK1-Rac signaling as an HER2 effector pathway essential for HER2-mediated breast cancer progression to metastasis and offers a therapeutic opportunity to limit the spread of metastatic breast cancers.ErbB2 | DOCK180 | RhoGEF | tumorigenesis D espite breakthroughs in the treatment of breast cancer, the most prevalent cancer in women, progression of the disease remains an important cause of death. Virtually all fatalities can be attributed to complications due to the appearance of secondary tumors at distant sites. The identification and therapeutic targeting of proteins regulating the metastatic step is therefore a priority for improving the lifespan of afflicted patients (1). Two major breast cancer subtypes, basal-like and HER2 + , are linked to aggressive and recurrent primary and metastatic tumors, and ultimately, to poor survival (2). HER2 is a member of the EGF receptor family of receptor tyrosine kinases (RTKs) also comprising HER1, HER3, and HER4 (3). Amplification of the HER2 locus, or aberrant expression of its protein product, is observed in nearly 20% of human breast cancers (4). Mouse models expressing various forms of HER2 in the mammary gland recapitulate most aspects of the human disease, including metastasis, and are powerful tools to gain insight into signaling pathways controlling tumorigenesis in vivo (5). Nonetheless, regulators of HER2-mediated metastasis remain poorly characterized.Metastasis is a complex and deadly, yet ine...

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“…Genes upregulated more than fivefold in the mammary glands of MMTV-Cre Brca1 Co/Co mice at day 1 of lactation include Cdkn1A (p21, up 16.3-fold), a cell cycle regulated that has previously been shown to be upregulated upon Brca1 repression (Hakem et al, 1996) and that has been implicated in breast cancer (Weiss, 2003); interferon-stimulated gene 15 (Isg15, up 10.9-fold) and the gene encoding the Isg15-interacting protein Ubp43 (up eightfold), the former being a ubiquitin-like gene implicated in immune response to viruses and in breast cancer (Bektas et al, 2008); oligoadenylate synthetase 1G (up 9.2-fold) and 1A (up 5.7-fold), an interferon-induced enzyme implicated in nucleotide metabolism and expressed in the mammary gland (Maia et al, 2008) and induced upon irradiation of human breast cancer cell lines (Tsai et al, 2007); and c-kit (up 5.58-fold), a hematopoietic stem cell marker that is overexpressed in undifferentiated mammary tumours (Tsuda et al, 2005) and functions as an oncogene in mammary epithelial cells (Tsuda et al, 2005;Raafat et al, 2007). Taken together, these genes suggest a role for Brca1 in the immune response and cancer.…”

Section: (A) Endogenousmentioning

confidence: 99%

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

Cited by 100 publications

References 32 publications

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

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

Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

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