This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2572

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 Increased, Invasion

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

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

Due to the extensive robust and concordant literature of the link between activation of the AhR-increased cell motility-increased invasion-breast cancer progression, the confidence in these key events was rated as high. However, due to the use of ligands to activate the AhR, it cannot be completely ruled out that alternative pathways (independent of the AhR) can also contribute to these features. For instance, 2 main pathways seem to explain this increase in migration and invasion: the c-Src/HER1/STAT5b, and ERK1/2 pathways. Yet, these pathways seem only to explain the relation between the AhR activation and cell migration / invasion, when the ligand used is hexachlorobenzene, an organochlorinated pesticide (Pontillo et al., 2011 AprMiret et al., 2016 JulPontillo et al., 2013 May 1). Even though alternative mechanisms may present themselves, all studies blocked the AhR pathway and found a decrease in cell migration/invasion. The evidence for alternative mechanisms was therefore classified as “moderate” and the biological plausibility of KER was also classified as “moderate”.

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

The activation of the AhR through the use of different ligands (benzophenone, butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, chlorpyrifos, TCDD) or the blockage of the AhR (silencing, KO or antagonism) increased or decreased cell invasion, respectively (Parks et al., 2014 NovQin et al., 2011 Oct 20Nguyen et al., 2016 Nov 15Miret et al., 2016 JulShan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1Miller et al., 2005Belguise et al., 2007 Dec 15Yamashita et al., 2018 May 1Miret et al., 2020 May). The dose–response concordance for cell invasion was demonstrated using increasing doses of hexachlorobenzene, benzo[a]pyrene, chlorpyrifos and TCDD (Miret et al., 2016 JulShan et al., 2020 NovPontillo et al., 2013 May 1Miller et al., 2005Miret et al., 2020 May). To further explore cell invasion, Nguyen et al. created a model of a lymphatic barrier using a three-dimensional lymph endothelial cell as a monolayer co-cultured with spheroids of MDA-MB231 cells (Nguyen et al., 2016 Nov 15). They found that silencing or antagonizing the AhR (DIM) or activating the AhR (FICZ) respectively decreased or increased invasion of the lymphatic barrier.

On an organ level, in vivo, an increase in metastasis has been found in mice and zebrafish after the activation of the AhR with different ligands (butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, TCDD) (Goode et al., 2014Shan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1). In the zebrafish model, Narasimham et al. treated the animals either with triple negative MDA-MB-231 cells only (untreated) or with MDA-MB-231 cells treated with an AhR inhibitor (CB7993113 or CH22319) (Narasimhan et al., 2018 May 7). Untreated fish had significantly more metastasis (OR = 9, IC95%=3–35). Similar results were found using mice models (Goode et al., 2014Shan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1).

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