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Relationship: 2569

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, AhR leads to Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Activation of the AhR leading to breast cancer adjacent High Louise Benoit (send email) Under Development: Contributions and Comments Welcome Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adults

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

KER 2569  Activation of the AhR leads to decreased apoptosis

Several studies have found that the activation of the AhR by stressors such as TCDD, can promote a decrease in apoptosis (KER1), which is a deleterious event with regards to cancer (Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015). Additionally, an increase in cell death was found when blocking the AhR pathway using AhR silencing (RNA interference or knock-out), knockout cell lines or antagonists (CH223191 or alpha-naphthoflavone) (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018). The most frequently used assay to evaluate apoptosis was cytometry with the use of Annexin V: this was performed with ER-positive cells lines (MCF-7, T-47D), triple negative cell lines (MDA-MB-231, HS 578), cells over-expressing the Her2 (SK-BR-3) and cells lines derived from cancer samples from patients (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018Fujisawa et al., 2011).

The concordance of the evidence was classified as “moderate” since the aim of most studies was to evaluate the capacity to survive in an apoptosis-promoting environment (i.e., chemotherapeutic drugs). Indeed, they assessed the resistance to chemotherapy agents such as doxorubicin and paclitaxel and found that the concomitant inactivation of the AhR pathway could decrease the resistance to these chemotherapy agents through an increase in cell death when compared to cells with a functional (or expressed at sufficient levels) AhR (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018Fujisawa et al., 2011). Since the environment was modified by the presence of chemotherapy, the hypothesis of an alternative pathway cannot be completely discarded. It must be noticed that the exact biological mechanisms linking the activation of the AhR to the decrease in apoptosis remains unclear. Indeed, Anderson et al. suggested that the AhR interacts with the glucocorticoid receptor (GR) and the hypoxia inducible factor-2α (HIF-2α) (Regan Anderson et al., 2018). The presence of the GR is associated with a poor prognosis, notably in triple negative breast cancer (Pan et al., 2011Moran et al., 2000 Feb 15). Indeed, this receptor is involved in survival and resistance to chemotherapy through up-regulation of c-myc, Bcl2 and Kruppel-like factor 5 (Pan et al., 2011Wu et al., 2004Li et al., 2017). Both GR and HIF 2α could be up regulated by the AhR. They then activate Brk (also known as PTK6), a ligand of EGFR (epidermal growth factor receptor), involved in the inhibition of apoptosis (Regan Anderson et al., 2018Li et al., 2012). Another possible mechanism suggested by Bekki et al. is that the decrease in apoptosis was caused by the induction of cyclooxygenase 2 (COX-2) and the NF-κB subunit RelB (Bekki et al., 2015). They both prevent apoptosis through induction of Bcl2, an anti-apoptotic factor (Tsujii and DuBois, 1995Vogel et al., 2007Thomas et al., 2020Baud and Jacque, 2008 DecDemicco et al., 2005 NovWang et al., 2007 AprLiu et al., 2001 May 25).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help