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Relationship: 3138

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

Increased, Invasion leads to Metastasis, Breast Cancer

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, Invasion

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Metastasis, Breast Cancer

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 metastatic breast cancer	adjacent	High	High	Louise Benoit (send email)	Under Development: Contributions and Comments Welcome	Under Review

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
human	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	High

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

An increased likelihood of metastasis is a major consequence of increased organ invasion in breast cancer through:

Access to Dissemination Routes: Organ invasion allows cancer cells to breach the physical barriers of the breast tissue and reach lymphatic or blood vessels. These vessels act as highways for cell transport throughout the body. Without organ invasion, cancer cells remain confined to the primary tumor and cannot enter the circulation. This is a crucial step for dissemination and potential metastasis formation in distant organs.
Selection for Metastatic Traits such as increased motility, enhanced adhesion, ability to survive in the bloodstream (resistance to anoikis). Cells possessing these advantageous traits are more likely to survive the harsh conditions of the bloodstream and potentially establish metastases in distant organs. [Gupta & Massague, 2006]
Tumor Microenvironment Modulation: During organ invasion, cancer cells interact with and modify the surrounding microenvironment. This can involve releasing various factors that i) promote angiogenesis, ii) suppress the immune system and iii) condition distant organs (niche)
Increased Number of "Seed" Cells: A larger tumor with increased organ invasion provides a larger pool of cancer cells that can potentially undergo the metastatic cascade. This increases the statistical probability that at least some cells will successfully navigate the complex steps involved in metastasis, ultimately leading to a higher chance of developing distant metastases.

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

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Observational Studies: Numerous studies have consistently shown a strong correlation between larger tumor size and higher stage (indicating greater local invasion) in breast cancer and a significantly increased risk of developing distant metastases. [Esteva et al., 2010, Edge & Compton, 2010]. The presence of cancer cells in the lymph nodes near the primary tumor, an indicator of lymphatic invasion, is also associated with a higher risk of developing distant metastases. [National Cancer Institute, 2023]
Retrospective Analyses: Studies analyzing patient data often demonstrate that individuals with breast cancer exhibiting deeper invasion or involvement of surrounding tissues have a greater likelihood of developing distant metastases compared to those with limited invasion. [Rakha et al., 2008]
Gene Expression Profiling: Studies comparing the gene expression profiles of metastatic and non-metastatic breast cancer have identified upregulation of genes associated with motility, invasion, EMT [Prat et al., 2010]
In Vitro and In Vivo Models: Laboratory models using breast cancer cell lines have demonstrated that enhancing the invasive capacity of these cells (e.g., through specific genetic modifications) can increase their ability to metastasize in vivo (living organisms). [Gupta & Massagué, 2006]
Clinical Practice:Treatment decisions for breast cancer often consider the extent of organ invasion alongside other factors. Cancers with higher invasion are often classified as higher stage and might require more aggressive treatment regimens due to the increased risk of metastasis. [National Cancer Institute, 2023]. Breast cancers classified as T3 or T4 (larger tumor size or extensive local invasion) have a significantly higher risk of developing distant metastases compared to T1 or T2 (smaller tumor size or limited local invasion) cancers. [National Cancer Institute, 2023]

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

Not a Direct Cause-and-Effect Relationship: Increased organ invasion is not a direct guarantee of metastasis. Other factors, such as the genetic makeup of the cancer cells, the patient's immune system, and the presence of supportive microenvironments in distant organs, also play vital roles in determining metastatic potential. Some breast cancers with limited invasion can still metastasize, and not all large, invasive tumors ultimately develop distant metastases.
Stage and Size Don't Always Reflect True Invasion: Tumor stage and size are used as indicators of local invasion but might not always accurately reflect the biological aggressiveness of the cancer cells. Certain tumors might exhibit extensive local growth without necessarily possessing the necessary traits for successful dissemination and metastasis.
Heterogeneity within Tumors: Breast tumors are often heterogeneous, meaning they contain populations of cells with varying characteristics and metastatic potential. Even within a large, invasive tumor, only a subset of cells may possess the specific traits required for successful metastasis.
Limitations of Observational Studies: While observational studies provide valuable evidence, they are correlational in nature and cannot establish causality. There might be unidentified confounding factors contributing to the observed association between increased invasion and metastasis.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. 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

Human

References

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

Edge, S. B., & Compton, C. C. (2010). The American Joint Committee on Cancer (AJCC) staging manual and the future of TNM. Annals of Surgical Oncology, 17(6 Suppl 3), S147-S156

Weaver, A. M., et al. (2011. Forcing it to fit: Fitting heterogeneity into the cancer framework: The case of metastasis. Nature Reviews Cancer, 11(6), 391-402. https://pubmed.ncbi.nlm.nih.gov/21555865/

Prat, A., et al. (2010). Phenotypic and molecular characteristics of collagen-type I-invading cells in human breast cancer. Oncogene, 29(37), 5372-5382. [https://pubmed.ncbi.nlm.nih.gov/20639870/]

Esteva, A., et al. (2010). A large-scale study of HER2 status in relation to prognosis and treatment of breast cancer. Journal of Clinical Oncology, 28(2), 343-350. https://pubmed.ncbi.nlm.nih.gov/19920223/

Gupta, G. P., & Massagué, J. (2006). Cancer metastasis: Building a framework for the future of therapy. Nature, 445(7128), 717-721. https://www.nature.com/articles/nature05395

National Cancer Institute. (2023, January 11). Stages of breast cancer. https://www.cancer.gov/types/breast/hp