The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

Kariri, Yousif; Alsaleem, Mansour; Joseph, Chitra; Alsaeed, Sami; Aljohani, Abrar; Shiino, Sho; Mohammed, Omar J.; Toss, Michael S.; Green, Andrew; Rakha, Emad A.

doi:10.1007/s10549-020-05955-1

Cited by 31 publications

(30 citation statements)

References 63 publications

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“…Expression of IFI27 in some studies is correlated with decreased proliferation and migration (40,41), and in others with increased tumorigenesis and migration and decreased patient survival (42)(43)(44). ISG15 expression is correlated with increased invasion, induction of M2-like macrophages, and decreased patient survival (45,46). IFITM1 is also correlated with increased tumorigenesis and invasion (47).…”

Section: Discussionmentioning

confidence: 99%

RhoC Modulates Cell Junctions and Type I Interferon Response in Aggressive Breast Cancers

et al. 2021

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Metastases are the leading cause of death in cancer patients. RhoC, a member of the Rho GTPase family, has been shown to facilitate metastasis of aggressive breast cancer cells by influencing motility, invasion, and chemokine secretion, but as yet there is no integrated model of the precise mechanism of how RhoC promotes metastasis. A common phenotypic characteristic of metastatic cells influenced by these mechanisms is dysregulation of cell-cell junctions. Thus, we set out to study how RhoA- and RhoC-GTPase influence the cell-cell junctions in aggressive breast cancers. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM 149 and MDA 231 breast cancer cells results in increased normalization of junctional integrity denoted by junction protein expression/colocalization. In functional assessments of junction stability, RhoC knockout cells have increased barrier integrity and increased cell-cell adhesion compared to wild-type cells. Whole exome RNA sequencing and targeted gene expression profiling demonstrate decreased expression of Type I interferon-stimulated genes in RhoC knockout cells compared to wild-type, and subsequent treatment with interferon-alpha resulted in significant increases in adhesion and decreases in invasiveness of wild-type cells and a dampened response to interferon-alpha stimulation with respect to adhesion and invasiveness in RhoC knockout cells. We delineate a key role of RhoC-GTPase in modulation of junctions and response to interferon, which supports inhibition of RhoC as a potential anti-invasion therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

RhoC Modulates Cell Junctions and Type I Interferon Response in Aggressive Breast Cancers

et al. 2021

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“…Eleven of these genes, belonging either to the interferon, antiviral response, or the cytosolic DNA-sensing pathways, were chosen to validate their preferential activation in 4T1/IR-A cells. These genes included: IFIT1, IFIT3 [27], IFI44 [28], IRGM1 [29], NMI [30], ISG15 [31], LGALS3BP [32], IRF9 [33], STAT1 [34], EIF2AK2/PKR [35], DDX58/RIG-I [35]. Six of these 11 genes have been previously described as part of the so-called IFN-related DNA-damage resistance signature (IRDS), which has been associated with resistance to chemo-and radiotherapy (see Discussion).…”

Section: Validation Of Rna Seq Analysismentioning

confidence: 99%

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Vella

Giuliano

Ferlita

et al. 2021

Cells

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The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.

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“…The most highly variable features in both samples were protein-coding genes known to be associated with cancer. These include genes such as PAEP, which encodes the protein glycodelin, a lipocalin protein associated with reproductive cancers including breast cancer [37], ISG15, a prognostic marker in breast cancer [38], and ANKRD1, which has been associated with lung and ovarian cancer [39,40] (Figure 2A). Cell type annotation did not result in meaningful calls.…”

Section: Quality Controlmentioning

confidence: 99%

Single-Cell RNA-Seq Reveals Heterogeneous lncRNA Expression in Xenografted Triple-Negative Breast Cancer Cells

Pinkney

Black

Diermeier

2021

Biology

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Breast cancer is the most commonly diagnosed cancer in the world, with triple-negative breast cancer (TNBC) making up 12% of these diagnoses. TNBC tumours are highly heterogeneous in both inter-tumour and intra-tumour gene expression profiles, where they form subclonal populations of varying levels of aggressiveness. These aspects make it difficult to study and treat TNBC, requiring further research into tumour heterogeneity as well as potential therapeutic targets and biomarkers. Recently, it was discovered that the majority of the transcribed genome comprises non-coding RNAs, in particular long non-coding RNAs (lncRNAs). LncRNAs are transcripts of >200 nucleotides in length that do not encode a protein. They have been characterised as regulatory molecules and their expression can be associated with a malignant phenotype. We set out to explore TNBC tumour heterogeneity in vivo at a single cell level to investigate whether lncRNA expression varies across different cells within the tumour, even if cells are coming from the same cell line, and whether lncRNA expression is sufficient to define cellular subpopulations. We applied single-cell expression profiling due to its ability to capture expression signals of lncRNAs expressed in small subpopulations of cells. Overall, we observed most lncRNAs to be expressed at low, but detectable levels in TNBC xenografts, with a median of 25 lncRNAs detected per cell. LncRNA expression alone was insufficient to define a subpopulation of cells, and lncRNAs showed highly heterogeneous expression patterns, including ubiquitous expression, subpopulation-specific expression, and a hybrid pattern of lncRNAs expressed in several, but not all subpopulations. These findings reinforce that transcriptionally defined tumour cell subpopulations can be identified in cell-line derived xenografts, and uses single-cell RNA-seq (scRNA-seq) to detect and characterise lncRNA expression across these subpopulations in xenografted tumours. Future studies will aim to investigate the spatial distribution of lncRNAs within xenografts and patient tissues, and study the potential of subclone-specific lncRNAs as new therapeutic targets and/or biomarkers.

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The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

Cited by 31 publications

References 63 publications

RhoC Modulates Cell Junctions and Type I Interferon Response in Aggressive Breast Cancers

RhoC Modulates Cell Junctions and Type I Interferon Response in Aggressive Breast Cancers

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Single-Cell RNA-Seq Reveals Heterogeneous lncRNA Expression in Xenografted Triple-Negative Breast Cancer Cells

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