Upregulated &lt;b&gt;&lt;i&gt;EBI3&lt;/i&gt;&lt;/b&gt; Correlates with Poor Outcome and Tumor Progression in Breast Cancer

Jiang, Jingjing; Liu, Xiangyong

doi:10.1159/000484935

Cited by 11 publications

(11 citation statements)

References 26 publications

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“…2B). Transcripts identified in Her2-NLP treated groups relative to either untreated or empty-NLP treated factors overlapped with previously reported screens for acinar morphogenesis (EBI3, CCL5) 28 and for residual disease in Her2+ breast cancer (CCL5 29,30 ), breast cancer outcome (EBI3 31–33 ) and metastasis (TGM2 34 , EBI3 33,35 ).…”

Section: Resultssupporting

confidence: 78%

Nanolipoprotein mediated Her2 protein transfection induces malignant transformation in human breast acinar cultures

Evans

Coleman

et al. 2020

Preprint

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Her2 overexpression is associated with an aggressive form of breast cancer and malignant transformation. We sought to determine if a nano-carrier system could introduce Her2 protein to non-malignant cells and determine the effects on cell phenotype and transcriptome. With stimulation with Her2-NLPs, we observed uptake of Her2 protein and a decreased probability of individual non-malignant cells forming polar growth arrested acinar-like structures. The NLP delivery system alone or Her2-NLPs plus trastuzumab showed no effect on acinar organization rate. Transcriptomics revealed essentially no effect of empty NLPs versus untreated cells whereas Her2-NLPs versus either untreated or empty NLP treated cells revealed upregulation of several factors associated with breast cancer. Pathway analysis also suggested that known nodes downstream of Her2 were activated in response to Her2-NLP treatment. This suggests that Her2-NLPs are sufficient for malignant transformation of non-malignant cells and that this system offers a new model for studying cell surface receptor signaling without genomic modification or transformation techniques.

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Section: Resultssupporting

confidence: 78%

Nanolipoprotein mediated Her2 protein transfection induces malignant transformation in human breast acinar cultures

Evans

Coleman

et al. 2020

Preprint

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“…Why the latter occurs remains to be investigated and explained. Given that as a self-standing molecule EBI3 has been, for example, involved in the pathogenesis of rheumatoid arthritis, 48 inflammatory bowel disease, 49 systemic sclerosis, 12 and cardiac inflammation, 50 as well in growth-promoting activity of lung 51 breast, 52 and colorectal cancer, 53…”

Section: Discussionmentioning

confidence: 99%

“…Why the latter occurs remains to be investigated and explained. Given that as a self‐standing molecule EBI3 has been, for example, involved in the pathogenesis of rheumatoid arthritis, 48 inflammatory bowel disease, 49 systemic sclerosis, 12 and cardiac inflammation, 50 as well in growth‐promoting activity of lung 51 breast, 52 and colorectal cancer, 53 other than representing a novel diagnosis marker in Burkitt and diffuse large B‐cell lymphoma, 54 further studies are necessary to clarify what is the effective function and biologic meaning of neutrophil‐derived EBI3 under these latter and other circumstances.…”

Section: Discussionmentioning

confidence: 99%

Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39

Cassatella

Gardiman

Arruda‐Silva

et al. 2020

Journal of Leukocyte Biology

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The IL-12 family of cytokines plays crucial functions in innate and adaptive immunity. These cytokines include heterodimers sharing distinct (IL-12A, IL-23A, and IL-27A) with two (IL-12B and Epstein-Barr virus induced gene 3 [EBI3]) chains, respectively, IL-12 (IL-12B plus IL-12A) and IL-23 (IL-12B plus IL-23A) sharing IL-12B, IL-27 (EBI3 plus IL-27A), IL-35 (EBI3 plus IL-12A), and IL-39 (EBI3 plus IL-23A) sharing EBI3. In this context, we have recently reported that highly pure neutrophils incubated with TLR8 agonists produce functional IL-23. Previously, we showed that neutrophils incubated with LPS plus IFN for 20 h produce IL-12. Herein, we investigated whether highly pure, TLR8-activated, neutrophils produce EBI3, and in turn IL-27, IL-35, and IL-39, the IL-12 members containing it. We report that neutrophils incubated with TLR8 ligands, TNF and, to a lesser extent, LPS, produce and release remarkable amounts of EBI3, but not IL-27A, consequently excluding the possibility for an IL-27 production. We also report a series of unsuccessful experiments performed to investigate whether neutrophil-derived EBI3 associates with IL-23A to form IL-39. Furthermore, we show that neutrophils incubated with IFN in combination with either TLR8 or TLR4 ligands express/produce neither IL-12, nor IL-35, due to the inability of IFN , contrary to previous findings, to activate IL12A transcription. Even IL-27 was undetectable in supernatants harvested from IFN plus R848-treated neutrophils, although they were found to accumulate IL27A transcripts. Finally, by immunohistochemistry experiments, EBI3-positive neutrophils were found in discrete pathologies only, including diverticulitis, cholecystitis, Gorham disease, and Bartonella Henselae infection, implying a specific role of neutrophil-derived EBI3 in vivo.

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“…Early findings point to a role for IL-35 in promoting cancer development (Figure 2); expression of p35, but not p28, was correlated with EBI3 in Hodgkin lymphoma and nasopharengeal carcinoma (112, 127). In breast cancer, EBI3 levels positively correlate with p35, however no significant correlation between EBI3 and p28 was detected, implicating a role for IL-35 rather than IL-27 (128). The correlation between elevated levels of EBI3 and p35 rather than p28 may hold potential information to how a tumor is able to influence the TME cytokine profile to promote tumorigenesis.…”

Section: Il-27 Il-30 and Il-35: Influencing Cancer Developmentmentioning

confidence: 99%

IL-27, IL-30, and IL-35: A Cytokine Triumvirate in Cancer

et al. 2019

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The role of the immune system in anti-tumor immunity cannot be overstated, as it holds the potential to promote tumor eradication or prevent tumor cell escape. Cytokines are critical to influencing the immune responses and interactions with non-immune cells. Recently, the IL-12 and IL-6 family of cytokines have accumulated newly defined members each with specific immune functions related to various cancers and tumorigenesis. There is a need to better understand how cytokines like IL-27, IL-30, and IL-35 interact with one another, and how a developing tumor can exploit these interactions to enhance immune suppression. Current cytokine-based immunotherapies are associated with cytotoxic side effects which limits the success of treatment. In addition to this toxicity, understanding the complex interactions between immune and cancer cells may be one of the greatest challenges to developing a successful immunotherapy. In this review, we bring forth IL-27, IL-30, and IL-35, “sister cytokines,” along with more recent additions to the IL-12 family, which serve distinct purposes despite sharing structural similarities. We highlight how these cytokines function in the tumor microenvironment by examining their direct effects on cancer cells as well their indirect actions via regulatory functions of immune cells that act to either instigate or inhibit tumor progression. Understanding the context dependent immunomodulatory outcomes of these sister cytokines, as well as their regulation within the tumor microenvironment, may shed light onto novel cancer therapeutic treatments or targets.

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Upregulated <b><i>EBI3</i></b> Correlates with Poor Outcome and Tumor Progression in Breast Cancer

Cited by 11 publications

References 26 publications

Nanolipoprotein mediated Her2 protein transfection induces malignant transformation in human breast acinar cultures

Nanolipoprotein mediated Her2 protein transfection induces malignant transformation in human breast acinar cultures

Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39

IL-27, IL-30, and IL-35: A Cytokine Triumvirate in Cancer

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