A key genomic subtype associated with lymphovascular invasion in invasive breast cancer

Kurozumi, Sasagu; Joseph, Chitra; Sonbul, Sultan; Alsaeed, Sami; Kariri, Yousif; Aljohani, Abrar; Raafat, Sara; Alsaleem, Mansour; Ogden, Angela; Johnston, Steven J.; Aleskandarany, Mohammed A.; Fujii, Takaaki; Shirabe, Ken; Caldas, Carlos; Ashankyty, Ibraheem; Dalton, Leslie W.; Ellis, Ian O.; Desmedt, Christine; Green, Andrew; Mongan, Nigel P.; Rakha, Emad A.

doi:10.1038/s41416-019-0486-6

Cited by 29 publications

(26 citation statements)

References 36 publications

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“…Our group has recently published a bioinformatics study using RNA expression data to identify differentially expressed genes in LVI-positive and LVI-negative cases. Following a stringent approach, 99 genes were demonstrated as significantly associated with BC LVI whether being upregulated or downregulated [109].…”

Section: Key Lvi-related Biomarkersmentioning

confidence: 99%

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

et al. 2020

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Lymphovascular invasion (LVI) is associated with poor outcome in breast cancer (BC); however, its underlying mechanisms remain ill-defined. LVI in BC develops through complex molecular pathways involving not only the interplay with the surrounding microenvironment along with endothelial cells lining the lymphovascular spaces but also changes in the malignant epithelial cells with the acquisition of more invasive and migration abilities. In this review, we focus on the key features that enable tumour cell detachment from the primary niche, their migration and interaction with the surrounding microenvironment as well as the crosstalk with the vascular endothelial cells, which eventually lead to intravasation of tumour cells and LVI. Intravascular tumour cell survival and migration, their distant site extravasation, stromal invasion and growth are part of the metastatic cascade. Cancer cell migration commences with loss of tumour cells' cohesion initiating the invasion and migration processes which are usually accompanied by the accumulation of specific cellular and molecular changes that enable tumour cells to overcome the blockades of the extracellular matrix, spread into surrounding tissues and interact with stromal cells and immune cells. Thereafter, tumour cells migrate further via interacting with lymphovascular endothelial cells to penetrate the vessel wall leading ultimately to intravasation of cancer cells. Exploring the potential factors influencing cell migration in LVI can help in understanding the underlying mechanisms of LVI to identify targeted therapy in BC.

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Section: Key Lvi-related Biomarkersmentioning

confidence: 99%

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…A previous study, reported by our team, has elucidated the mechanistic association between gene expression and LVI positivity [ 5 ]. The 99 deferentially expressed genes (DEGs) that showed association with LVI exhibited 42 significantly upregulated genes and 57 significantly downregulated genes based on weighted average differences (WAD) [ 5 , 6 ]. Furthermore, when gene set enrichment analysis (GSEA) [ 7 ] was applied to the molecular panel previously identified by WAD approach, cell migration was the top of the main regulators of the gene panel.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous studies aiming to identify the driver of LVI in BC [ 1 , 5 ], ISG15 was in the differentially identified genes associated with LVI. This study aimed to validate the prognostic significance of ISG15 defined by our gene signature [ 5 ] and evaluate its association with well-established prognostic variables including LVI, relevant biomarkers related to ISG15 function/expression and patient outcome.…”

Section: Introductionmentioning

confidence: 99%

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

Kariri

Alsaleem

Joseph

et al. 2020

Breast Cancer Res Treat

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Background Lymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC. Methods The prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan–Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated. Results High mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival. Conclusion This study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.

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“…Tumor cell invasion involves their migration and penetration into neighboring tissues. Lymphovascular invasion is, in general, the first stage of carcinogenic events that initiate tumor metastasis [3]. The initial step of invasion is characterized by the breakdown of the basement membrane, a sheet-like structure of the extracellular matrix secreted by the epithelium [4].…”

Section: Introductionmentioning

confidence: 99%

A Novel Synthetic Compound (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile Inhibits TNFα-Induced MMP9 Expression via EGR-1 Downregulation in MDA-MB-231 Human Breast Cancer Cells

Jeong

Jung

Lee

et al. 2020

IJMS

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Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and characterized its inhibitory effects on the motility and MMP2 and MMP9 expression of highly metastatic MDA-MB-231 breast cancer cells. We found that DK4023 inhibited tumor necrosis factor alpha (TNFα)-induced motility and F-actin formation of MDA-MB-231 cells. DK4023 also suppressed the TNFα-induced mRNA expression of MMP9 through the downregulation of the TNFα-extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR-1) signaling axis. These results suggest that DK4023 could serve as a potential platform compound for the development of novel chemopreventive/chemotherapeutic agents against invasive breast cancer.

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A key genomic subtype associated with lymphovascular invasion in invasive breast cancer

Cited by 29 publications

References 36 publications

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

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

A Novel Synthetic Compound (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile Inhibits TNFα-Induced MMP9 Expression via EGR-1 Downregulation in MDA-MB-231 Human Breast Cancer Cells

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