API

Relationship: 1908

Title

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Increased pro-inflammatory mediators leads to Increase, Cell Proliferation (Epithelial Cells)

Upstream event

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Increased pro-inflammatory mediators

Downstream event

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Increase, Cell Proliferation (Epithelial Cells)

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent Moderate Not Specified
Increased DNA damage leading to increased risk of breast cancer adjacent Moderate Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Pro-inflammatory factors increase proliferation.

Evidence Supporting this KER

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Biological Plausibility is High. Inflammation is generally understood to lead to proliferation during recovery from inflammation.

Biological Plausibility

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Biological Plausibility is High. Inflammation is generally understood to lead to proliferation during recovery from inflammation. Major inflammation-related transcription factors NF-kB, AP1, and STAT3 mediate proliferation and survival (Grivennikov, Greten et al. 2010). Inflammation enhances compensatory proliferation during wound healing including following inflammation-associated cell killing (Landen, Li et al. 2016), and contributes to proliferation via growth enhancing signals including changes to the microenvironment and promotion of stem-like characteristics (Grivennikov, Greten et al. 2010; Hanahan and Weinberg 2011; Kiraly, Gong et al. 2015). These effects can vary between tissues and in different contexts in ways that are not well understood (Grivennikov, Greten et al. 2010). In mammary gland and in mammary epithelial cells, inflammation-related transcription factor NF-kB and multiple cytokines promote proliferation and tumorigenesis (Connelly, Barham et al. 2011; Esquivel-Velazquez, Ostoa-Saloma et al. 2015).

Empirical Evidence

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Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Connelly, L., W. Barham, et al. (2011). "Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden." Oncogene 30(12): 1402-1412.

Esquivel-Velazquez, M., P. Ostoa-Saloma, et al. (2015). "The role of cytokines in breast cancer development and progression." J Interferon Cytokine Res 35(1): 1-16.

Grivennikov, S. I., F. R. Greten, et al. (2010). "Immunity, inflammation, and cancer." Cell 140(6): 883-899.

Hanahan, D. and R. A. Weinberg (2011). "Hallmarks of cancer: the next generation." Cell 144(5): 646-674.

Kiraly, O., G. Gong, et al. (2015). "Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo." PLoS Genet 11(2): e1004901.

Landen, N. X., D. Li, et al. (2016). "Transition from inflammation to proliferation: a critical step during wound healing." Cellular and molecular life sciences : CMLS 73(20): 3861-3885.