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Event: 1982

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

metastatic breast cancer

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Metastasis, Breast Cancer
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
DNA damage and metastatic breast cancer AdverseOutcome Agnes Aggy (send email) Under development: Not open for comment. Do not cite Under Development
AhR activation to metastatic breast cancer AdverseOutcome Evgeniia Kazymova (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human and other cells in culture human and other cells in culture High NCBI
human Homo sapiens High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Processs: metastasis of cancer cells                             Object:metastasis                    Process:Increased

Biological state: 

Metastasis, the process by which cancer cells spread from their site of origin to distant organs or tissues, is a complex and multifaceted biological phenomenon that poses a significant challenge in cancer management. Cancer metastasis represents a critical stage in the progression of the disease, often leading to poorer patient outcomes and decreased survival rates. Understanding the molecular and cellular mechanisms underlying metastasis is crucial for developing effective therapeutic strategies to combat advanced-stage cancers.

At the biological level, metastasis involves a series of sequential steps that cancer cells must undergo to successfully disseminate and colonize distant sites within the body. These steps include local invasion of surrounding tissues by cancer cells, intravasation into nearby blood or lymphatic vessels, survival and transport through the circulation, extravasation into distant tissues, and establishment of secondary tumors through proliferation and angiogenesis. Each of these steps is regulated by a complex interplay of genetic, epigenetic, and microenvironmental factors that influence the invasive and migratory properties of cancer cells.

The metastatic process is driven by a variety of molecular alterations that confer cancer cells with the ability to invade and metastasize. Key molecular mechanisms implicated in metastasis include dysregulated signaling pathways involved in cell adhesion, motility, and invasion, as well as genetic mutations and epigenetic modifications that promote tumor progression and metastatic spread. For example, alterations in genes encoding cell adhesion molecules such as E-cadherin, integrins, and cadherins can disrupt cell-cell and cell-matrix interactions, facilitating the detachment and dissemination of cancer cells from the primary tumor site.

Furthermore, the tumor microenvironment plays a critical role in regulating the metastatic behavior of cancer cells. Stromal cells, immune cells, and extracellular matrix components within the tumor microenvironment interact dynamically with cancer cells to modulate their invasive and migratory properties. Additionally, factors such as hypoxia, inflammation, and angiogenesis contribute to the formation of a pro-metastatic niche that supports the survival and outgrowth of disseminated cancer cells at distant sites.

In summary, metastasis is a complex biological process driven by genetic, molecular, and microenvironmental factors that enable cancer cells to spread and establish secondary tumors in distant organs or tissues. Understanding the underlying mechanisms of metastasis is essential for the development of targeted therapies aimed at disrupting key molecular pathways involved in this process, ultimately improving outcomes for patients with advanced-stage cancers.

Biological compartment


Role in general biology

Metastasis, although primarily studied in the context of cancer biology, also has relevance in general biology as it reflects fundamental biological processes such as cell migration, invasion, and tissue remodeling. Understanding these processes not only sheds light on cancer progression but also provides insights into various physiological and pathological phenomena in multicellular organisms.

1. Cell Migration: Cell migration is a fundamental process in various biological contexts, including embryonic development, wound healing, and immune responses. Metastasis involves the migration of cancer cells from the primary tumor to distant sites within the body, exploiting mechanisms similar to those used by normal cells during migration. Studying cancer metastasis can provide valuable insights into the molecular mechanisms underlying cell migration, including changes in cytoskeletal dynamics, cell adhesion, and signaling pathways that regulate cell motility.

2. Invasion and Extravasation: Cancer metastasis requires cancer cells to invade surrounding tissues, intravasate into blood or lymphatic vessels, survive in the circulation, and extravasate into distant tissues. These processes involve complex interactions between cancer cells and the surrounding microenvironment, including extracellular matrix components, immune cells, and stromal cells. Understanding the mechanisms of invasion and extravasation in cancer metastasis can provide insights into how cells navigate and interact with their microenvironment under physiological and pathological conditions.

3. Tissue Remodeling and Angiogenesis: Metastatic tumors undergo extensive tissue remodeling and angiogenesis to establish secondary growths at distant sites. This process involves the degradation of extracellular matrix components, the recruitment of blood vessels, and the formation of a supportive microenvironment for tumor growth. Similar processes occur during normal physiological events such as tissue repair and regeneration. By studying metastasis, researchers can gain insights into the molecular mechanisms underlying tissue remodeling and angiogenesis, which are critical for understanding various biological processes beyond cancer.

4. Cell-Cell and Cell-Matrix Interactions: Metastasis involves dynamic interactions between cancer cells and neighboring cells, as well as with components of the extracellular matrix. These interactions influence cell adhesion, migration, and invasion, and are mediated by various cell adhesion molecules, receptors, and signaling pathways. Understanding the mechanisms of cell-cell and cell-matrix interactions in metastasis can provide insights into how cells communicate and coordinate their behavior in different biological contexts, including embryonic development, tissue homeostasis, and disease processes.

In conclusion, while metastasis is a hallmark of cancer progression, it also reflects fundamental biological processes that are relevant in general biology. Studying metastasis not only advances our understanding of cancer biology but also provides insights into various physiological and pathological phenomena involving cell migration, invasion, tissue remodeling, and intercellular interactions.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Method/ measurement reference


Strength of evidence

Assay fit for purpose

Repeatability/ reproducibility

Direct measure

Cell line,humans,Human cell line studies

qRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, bioluminesence imaging,wound healing assay,Wound scratch & Transwell assay, Microarray,Immunofluorescence, Immunohistochemistry,






Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Increased metastasis of cancerous cells  is known to be highly conserved throughout evolution and is present from humans to invertebrates.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

The Adverse Outcome Pathway (AOP) holds substantial regulatory significance as a structured framework for understanding and predicting the biological sequence of events leading from DNA damage to a metastatic breast cancer. By elucidating the causal relationships between key events along the pathway, AOP offer a comprehensive understanding of toxicological mechanisms and provide a basis for informed decision-making in risk assessment and regulatory decision-making. AOPs facilitate the integration of diverse scientific data, enabling regulators to evaluate the potential impact of chemical exposures on human health and the environment. These pathways empower the development of targeted testing strategies, alternative methods, and safer chemical design, ultimately enhancing the efficiency and accuracy of risk assessment and regulatory policies.

Metastasis, the process by which cancer cells spread from the primary tumor to distant sites in the body, holds significant regulatory importance in cancer biology and beyond. Understanding the regulatory mechanisms underlying metastasis is crucial for developing effective therapeutic strategies and improving patient outcomes. Here are some key aspects of its regulatory significance:

1. Therapeutic Target Identification: Regulatory pathways governing metastasis represent potential targets for therapeutic intervention. By elucidating the signaling networks and molecular drivers involved in metastatic processes such as cell migration, invasion, and angiogenesis, researchers can identify druggable targets for the development of anti-metastatic therapies. Targeting these pathways can potentially inhibit the spread of cancer cells and prevent the formation of secondary tumors, thereby improving patient survival and quality of life.

2. Biomarker Discovery: Metastasis-specific biomarkers have diagnostic, prognostic, and therapeutic implications. Regulatory molecules or genetic signatures associated with metastatic potential can serve as biomarkers for predicting patient outcomes, stratifying patients for personalized treatment approaches, and monitoring disease progression. Biomarker discovery efforts aim to identify molecular signatures indicative of metastatic propensity, enabling early detection of metastasis and guiding treatment decisions.

3. Therapeutic Resistance Mechanisms: Metastatic tumors often exhibit resistance to conventional therapies, posing a significant clinical challenge. Regulatory mechanisms underlying therapy resistance in metastatic cancer cells, such as alterations in drug efflux pumps, DNA repair pathways, and apoptotic signaling, need to be elucidated. Understanding these resistance mechanisms can inform the development of novel therapeutic strategies to overcome drug resistance and improve treatment efficacy in metastatic cancer patients.

4. Microenvironment Modulation: The tumor microenvironment plays a crucial role in regulating metastasis by providing a supportive niche for cancer cell survival, proliferation, and dissemination. Regulatory factors within the tumor microenvironment, including stromal cells, immune cells, extracellular matrix components, and signaling molecules, influence metastatic progression. Targeting the tumor microenvironment to disrupt pro-metastatic signaling pathways or enhance anti-tumor immune responses represents a promising therapeutic approach to inhibit metastasis and improve treatment outcomes.

5. Epigenetic Regulation: Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA dysregulation, contribute to metastatic phenotypes by modulating gene expression programs associated with cell motility, invasion, and metastatic colonization. Understanding the epigenetic regulatory mechanisms driving metastasis can provide insights into novel therapeutic targets and strategies for epigenetic therapy in metastatic cancer.

In summary, metastasis exerts significant regulatory influence on cancer progression and treatment response. Elucidating the molecular and cellular regulatory mechanisms governing metastasis is essential for the development of targeted therapies, biomarker-driven treatment strategies, and interventions to overcome therapeutic resistance. By targeting metastasis-specific pathways and processes, researchers aim to improve patient outcomes and ultimately reduce the morbidity and mortality associated with metastatic cancer.


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

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

2. Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging biological principles of metastasis. Cell, 168(4), 670-691.

3. Steeg, P. S. (2016). Targeting metastasis. Nature Reviews Cancer, 16(4), 201-218.

4. Valastyan, S., & Weinberg, R. A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147(2), 275-292.

5. Massagué, J., & Obenauf, A. C. (2016). Metastatic colonization by circulating tumour cells. Nature, 529(7586), 298-306.

6. Psaila, B., & Lyden, D. (2009). The metastatic niche: adapting the foreign soil. Nature Reviews Cancer, 9(4), 285-293.

7. Leung, E. L., Fiscus, R. R., Tung, J. W., Tin, V. P., Cheng, L. C., Sihoe, A. D., ... & Wong, M. P. (2010). Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One, 5(11), e14062.

8. Joyce, J. A., & Pollard, J. W. (2009). Microenvironmental regulation of metastasis. Nature Reviews Cancer, 9(4), 239-252.

9. Chaffer, C. L., & Weinberg, R. A. (2011). A perspective on cancer cell metastasis. Science, 331(6024), 1559-1564.

10. Nguyen, D. X., Bos, P. D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer, 9(4), 274-284.